Background

Cancer is considered as the major cause of mortality in the worldwide. According to the global cancer statistics of the Global Cancer Observatory (GCO), there will be 18.1 million new cases and 9.6 million cancer deaths worldwide in 2018 (World Health Organization. Cancer. 2018; https://gco.iarc.fr/). The top 5 most prevalent cancers in the world are lung cancer (LC), breast cancer (BC), prostate cancer (PCa), colon cancer and gastric cancer (GC, Table 1). In China, LC and liver cancer were two of the top five causes of death leading to years of life lost (YLLs) in 2017 [1]. Environmental and genetic risk factors have been recognized as the two major risk factors resulting in various tumorigenesis and cancer progression. Recent decades have witnessed the molecular understanding of the mechanisms of numerous genetic factors in human cancer, such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), P53, NF-kB, STAT3, COX-2 and c-Myc. Apparently, PI3K/AKT pathway has gradually gotten a major focus of attention as it plays a crucial role in regulating diverse cellular functions, including metabolism, growth, proliferation, survival, transcription and protein synthesis.

Table 1 Incidence, mortality and genetic alteration of PI3K/AKT pathway by cancer site (https://gco.iarc.fr/; https://www.cbioportal.org/)
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The PI3Ks are a family of heterodimeric lipid kinases, which are grouped into class I, II, and III isoforms. Class IA subgroup of PI3Ks activated by receptor tyrosine kinases consist of a p110 catalytic subunit (p110α, PIK3CA; p110β, PIK3CB; p110δ, PIK3CD) and one of five p85-like regulatory subunits (p85α, p55α, p50α, PIK3R1; p85β, PIK3R2; p55γ, PIK3R3). Class IB subgroup of PI3Ks activated by G protein-coupled receptors consist of the catalytic subunit (p110γ, PIK3CG) and regulatory subunits (p101, PIK3R5; p87, PIK3R6). Class II PI3Ks comprises PI3K-C2α (PIK3C2A), β (PIK3C2B) and γ (PIK3C2G). And the single class III PI3K is hVPS34 (PIK3C3). When PI3K is activated by a variety of upstream cell-surface receptors, including growth factor, antigen, costimulatory, cytokine, chemokine, and Toll-like receptors (TLRs), class I PI3Ks catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) with phosphorylation at the D3 position of the inositol ring to the second messenger phosphatidylinositol 3,4,5-triphosphate (PIP3). Two PIP3-binding Pleckstrin homology (PH) domain-containing proteins linked to PI3K activity in all cells, including B cells, are the serine/threonine kinases AKT and phosphoinositide-dependent kinase-1 (PDK-1) [2,3,4,5].

AKT is an evolutionarily conserved serine protein kinase from the protein kinase AGC subfamily, which is composed of three conservative structure domains, including N-terminal PH domain, a short C-terminal tail containing a regulatory hydrophobic motif (HM) and a linker region with a central kinase catalytic domain [6]. AKT contains three highly conserved homologous subtypes, AKT1/PKBα (AKT1), AKT2/PKBβ (AKT2) and AKT3/PKBγ (AKT3). On the cell membrane, AKT is recruited via its PH domain ascribing to the accumulation of PI(3,4,5)P3 and PI(3,4)P2 (less extent), and plays a catalytic role by activating two regulatory sites, including a threonine phosphorylated by PDK1 at Thr308(AKT1), Thr309(AKT2), Thr305(AKT3) and a serine phosphorylated by the mammalian Target of Rapamycin (mTOR) Complex mTORC2 at Ser473(AKT1), Ser474(AKT2), Ser472(AKT3) respectively as well as specifically [7, 8]. Massive researches have shown that AKT regulates vital downstream effector molecules, such as FOXO, mTOR, GSK3b, and many other effectors via phosphorylation cascade reaction, which is modulated by lipid and protein phosphatases, to control cell growth, proliferation, survival, genome stability, glucose metabolism, and neovascularization [9,10,11,12]. However, the activities of these phosphatases are frequently lost or inactivated evidently in human cancer, followed by the result of AKT hyperactivation.

When talking about PI3K/AKT pathway, we have to mention phosphatase and tensin homolog deleted on chromosome 10 (PTEN), the primary negative regulator of the PI3K/AKT pathway. As a lipid phosphatase, PTEN directly suppresses the activation of PI3K/AKT pathway via converting the PIP3 generated by PI3K back to PIP2. The p85α regulatory subunit has a dual effect on the p110α catalytic subunit, since p85α inhibits the activity of p110α while it plays an important role in the stability of p110α. In addition, the p85α regulatory subunit has been proven to directly bind PTEN and enhance its activity to promote the conversion of PIP3 to PIP2 [13, 14]. Indeed, the abnormality of PTEN have been validated in diverse cancers, even directly related with carcinogenesis in some cancers.

Following the emerging alterations of PI3K/AKT pathway genes have been widely reported in cancers recently, the inhibitors of PI3K/AKT pathway have brought a new era for targeted therapy of cancer. Since the first approval of idelalisib (CAL-101) validated the druggability of the PI3K pathway, more and more PI3K inhibitors have been created. They are generally divided into pan-PI3K (targeting all four isoforms of class I PI3K), isoform-selective (targeting single isoform of class I PI3K) and dual inhibitors (highlighted by dual PI3K/mTOR inhibitors). Comparatively, the number of AKT inhibitors which have been explored in clinical trials is less than that of PI3K inhibitors. AKT inhibitors mainly include two separate classes: Allosteric inhibitors and ATP-competitive inhibitors. The formers prevent localisation of AKT by PH domain to the plasma membrane, thereby blocking AKT phosphorylation and activation. The latters targeting the phosphorylated conformation of AKT include first generation and second generation inhibitors [15, 16]. These PI3K/AKT inhibitors have shown their various aptitude for anticancer in preclinical experiments or clinical trials, even druggable value for the anticancer treatment.

In this review, we present the comprehensive work of PI3K/AKT pathway with a new perspective in various cancer sites, in which elevated PI3K/AKT pathway is considered as a hallmark. Firstly, we state the abnormalities of PI3K/AKT pathway and summarize the roles of PI3K/AKT in aberrant signaling cascades in human cancers. Furthermore, we list the involvement of the PI3K/AKT inhibitors in the clinical trials of targeted therapies in cancers. Meanwhile, we briefly provide preliminary findings in the context of resistance to targeted therapies. Finally, we discuss the confusion and the future of the PI3K/AKT pathway.

Recent studies and results

Profiling the PI3K/AKT pathway in the brain and central nervous system tumors

Considering that the incidence and mortality of the brain and central nervous system tumors is 1.6% and 2.5% respectively in the worldwide (https://gco.iarc.fr/, Table 1), particularly the most common primary malignant tumor, glioblastoma multiforme (GBM), contributes to the poor prognosis partly for its tolerance of radiation therapy, hyper-activation of PI3K/AKT pathway in GBM caused by the mutations of PIK3CA or PIK3R1 (18.3%) and other PI3K family genes (6.8%) has urged researchers to seek novel targeted treatments to control the disease [17,18,19]. Moreover, knockdown of PIK3CA or PIK3R1 significantly inhibits cell viability, migration and invasion in GBM cells via hypo-activation of AKT and FAK [20]. In addition, overexpression of p110β is more frequently detected in a series of GBM cell lines than in the patient tumor samples. PIK3CB knockdown suppresses cell proliferation and induces caspase-dependent apoptosis in GBM in vitro and vivo instead of suppressing GBM cell migration [21,22,23]. Therefore, PI3K inhibitors have been seriously studied in GBM for decades and some have achieved significant success in treating GBM.

As a matter of fact that more than 50 PI3K inhibitors have been designed and produced for cancer treatment, but only a minority of them such as BKM120, XL147, XL765 and GDC-0084 have successfully entered into clinical trials for GBM treatment (https://clinicaltrials.gov, Table 2) [18]. Some p110α isoform-selective inhibitors, such as A66 or PIK-75, could effectively suppress the GBM cell growth, survival and migration in vitro [24], while inhibition of p110β by TGX-221 only arrests cell migration, and inhibition of p110δ by IC87114 or CAL-101 moderately blocks cell proliferation and migration [22, 25]. However, PI3K inhibitors including A66 and BEZ235 are observed to increase the expression of cancer stem cell (CSC) genes (SOX2, OCT4 and MSI1) in GBM CSC models, which exhibit therapy resistance [26].

Table 2 Clinical trial of PI3K Inhibitors in cancers (as of December 2019) (https://clinicaltrials.gov)
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By the way, although AKT isoforms are observed to play different roles in GBM, including AKT3 delays tumor progression [27], as a matter of fact, the AKT inhibitor perifosine is tolerable but ineffective as monotherapy for GBM [28]. AKT inhibitors remain elusive and bear the weight of further examination in treating GBM.

Notably, building on that 22% genetic alterations of PTEN was detected in GBM (https://www.cbioportal.org, Table 1), especially deep deletion, which caused the loss of function of PTEN tumor suppressor, PTEN was deeply involved in the pathological effects of PI3K/AKT pathway in GBM [29]. Meanwhile, genetic loss of PTEN is associated with each subtype of GBM [30].

Additionally, glucose regulated protein 78 (GRP78) interacts with α2-macroglobulin to activate AKT1 via PDK1, as well as mTOR to enhance cancer cell proliferation and radiotherapy resistance in GBM [31,32,33]. Anti-GRP 78 antibody can restore cancer cells to sensitivity to radiation therapy, which inhibits cell proliferation and enhances apoptosis, and has the advantage of targeting against cancer cells without affecting normal cells. Moreover, combination of anti-GRP 78 antibody and radiation therapy (XRT) shows better inhibitory effect on tumor [31].

Compared to GBM, the genetic alteration of PIK3CA (2%) and PIK3R1 (0.3%) in medulloblastoma (MBM, Table 1), which is the most aggressive malignant brain tumor that highly occurs in children and survival rate can reach 70% after active treatment, are less frequently observed [34]. However, enhance phosphorylation of AKT via PI3K or mTOR to restrain GSK3 in MBM, which lead to SOX9 degradation is reduced due to the facts that FBW7 degrades SOX9 under the guidance of GSK3. The loss of FBW7 function increases SOX9 protein levels, increasing the malignancy of cancer and resistance to cisplatin [35]. As a major oncoprotein inhibitor, once FBW7 is deleted or mutated, it can cause tumors to occur directly [36, 37]. So targeted inhibition of the PI3K pathway has a bright therapeutic potential in MBM. Moreover, experiments show that combination of PI3K inhibitor, mTOR inhibitor and cisplatin can achieve better therapeutic effect [35], and how well LY3023414 works in recurrent MBM is being tested in an ongoing clinical trial (NCT03213678, Table 2).

Aberration of the PI3K/AKT pathway in the cancer of endocrine system

Thyroid cancer (TC) is the most common malignancy in the endocrine system with a global incidence rate of 3.1% but a relatively lower lethality (0.4%, Table 1). In view of the fact that follicular epithelial cell–derived TC accounts for > 95% of all thyroid malignancies, TC histologically comprises papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) [38]. Although PDTC and ATC only account for approximately 5%–10% of TC, but they have brought great clinical challenges since they beget two-thirds of TC-related deaths [39]. Obviously, the overall genetic alterations of PI3K/AKT pathway in TC are inconspicuous (Table 1), but genetic mutations in PI3K/AKT pathway are common in PDTC and ATC, specifically more common in ATC than in PDTC. Besides PIK3CA (18% vs. 2%) and PTEN (15% vs. 4%), mutations of PIK3C2G (6% vs. 1%), PIK3CG (6% vs. 1%), PIK3C3 (0 vs. 1%), PIK3R1 (0 vs. 1%), PIK3R2 (3% vs. 0), AKT3 (0 vs. 1%) are also observed in ATC and PDTC respectively [40]. REC8, TEKT4, ING5, c-Met, HPIP, PIG3, TBX1, CRLF1, INPP4B, MAPK4, miR-34a, -125b, -126, -145, -146b, -148a and -766, as well as lncRNA LINC003121, ABHD11-AS1, H19 and XIST regulate TC cell growth, tumor progression, migration, metastasis or epithelial–mesenchymal transition (EMT) through activating PI3K/AKT pathway [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. Actually, exclusive activating mutations of BRAF (60% vs. 33% and 38%) in PTC are more frequently observed than in PDTC and ATC [40], while mice experiments show that co-mutation of BRAF and PIK3CA can promote the development of lethal ATC, but neither BRAF nor PIK3CA mutations alone can [62]. In addition, mutations in BRAF and PIK3CA can activate the MAPK pathway and the PI3K/AKT pathway respectively and lead to the occurrence of ATC, whereas dual blocking PI3K and MAPK pathways can effectively inhibit ATC [63]. Dual PI3K/HDAC inhibitor CUDC-907 inhibits TC growth and metastases, and may be a promising treatment strategy for advanced, metastatic TC [64]. Moreover, whether CUDC-907 was safe and effective in ATC and PDTC patients had been attempted in a terminated clinical trial (NCT03002623) besides the clinical trial of BKM120 in patients with advanced or metastatic differentiated TCs (NCT01830504, Table 2).

Characterization of the PI3K/AKT pathway in the respiratory system tumor

The respiratory system tumors are composed of the upper respiratory tract tumors, such as nasopharyngeal carcinoma (NPC) and laryngeal cancer, and the lower respiratory tract tumors, which mainly refer to LC. Compared to the NPC and laryngeal cancer, LC is witnessed as the gender-free and world-wide cancer with the highest morbidity (11.6%) and mortality (18.4%, Table 1).

LC is classified into two categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) including three subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC) [65]. In the light of the fact that genetic alterations of PIK3CA (3% vs. 17%), PIK3R1 (2% vs. 1.8%), PIK3R2 (1.5% vs. 1.6%), AKT1 (0.5% vs. 2.1%), AKT2 (1.5% vs. 3%) and PTEN (8% vs. 6%) are observed in SCLC and NSCLC respectively (Table 1), the studies of treatment strategies of LC targeting PI3K/AKT pathway are in full swing. Apart from those widely recognized alterations, such as EGFR and KRAS gene mutations, MET amplification, EML4-ALK rearrangements in NSCLC, somatic mutations and amplification in PIK3CA are described in 3–10% vs. 35% of SCC and 0–2.7% vs. 7% of ADC respectively [66]. What’s more, the expression of PIK3IP1, a negative regulator of PI3K, which can combine the p110 catalytic subunit of PI3K heterodimers to inhibits the activity of PI3K catalytic, is significantly lower in ADC and other tumors tissues [67]. ROCK1, GPX1, PAX6-ZEB2 axis, miR-93 and -496, as well as LINC00665 participate in regulation of the growth, migration, tumorigenesis or chemoresistance of NSCLC through PI3K/AKT pathway [68,69,70,71,72,73]. Furthermore, IGF-1 activates PI3K/AKT/β-catenin axis, which promotes the symmetric cell division of lung CSC and expands CSC pool, to maintain tumorigenesis [74, 75]. Interestingly, GRP78 plays the same role in radiation resistance and survival of cells in NSCLC by activating AKT1 as in GBM [31]. Currently, the potential of PI3K/AKT inhibitors has been clinically evaluated in a considerable number of studies (Tables 2 and 3) with NSCLC patients. On the other hand, MCAM and EPHA3 mediate chemoresistance in SCLC via the PI3K/AKT pathway [76, 77]. Whether combining daily BKM120 with cisplatin and etoposide was safe and effective in extensive stage SCLC patients had been attempted in a completed clinical trial (NCT02194049, Table 3).

Table 3 Clinical trial of AKT Inhibitors in cancers (as of December 2019) (https://clinicaltrials.gov)
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NPC is a unique cancer prevalent in South-East Asia with strong etiological association with Epstein–Barr virus (EBV) exposure [78]. As expected, NPC has a relatively lower mutational burdens with PIK3CA mutations of 1.8% (Table 1), however, there are still numerous of researches involved in PI3K/AKT pathway in NPC. Not only is hyperactivation of PI3K/AKT pathway in relation to NPC progression and prognosis [79], but FOXO1, CHL1, PNUTS, VPS33B interacts with NESG1, RBM3, ARHGAP42 and LncRNA ZFAS1 also display their influence on the proliferation, growth, invasion, metastasis, EMT, chemosensitivity or radio-resistance of NPC cells via PI3K/AKT pathway [80,81,82,83,84,85,86]. Moreover, miR-205-5p induces EMT by targeting PTEN via PI3K/AKT pathway in cisplatin-resistant NPC cells [87].

Typically presenting as a form of squamous cell carcinoma, laryngeal cancer is one of common malignancies in the head and neck, which is partly associated with human papillomavirus (HPV) [78, 88, 89]. A series of studies show the mutational events of PI3K pathway (30.5%) in 151 head and neck squamous cell carcinomas (HNSCCs) containing 29 laryngeal squamous cell carcinomas (LSCCs), particularly PIK3CA mutations of 12.6% [90,91,92]. Furthermore, profiling 279 HNSCCs containing 72 LSCCs, alteration events of PIK3CA (34% vs. 56%), PIK3R1 (1 vs. 3%) and PTEN (12% vs. 6%) are displayed in 243 HPV (−) and 36 HPV (+) HNSCCs respectively [93]. Additionally, MMP2/3, MEOX2, miR-145 and -138 regulate the growth, apoptosis or migration of LSCC cells by targeting the PI3K/AKT pathway [94,95,96,97].

Herein, clinical trials of BKM120 (Table 2) in NPC and LSCC patients may provide the feasibility of new treatment strategies. Even more, the safety and efficacy of AKT inhibitor MK2206 in NPC patients had been evaluated in a completed clinical trial (Table 3).

Deregulation of the PI3K/AKT pathway in digestive system tumors

It’s well established that the global health status is jeopardized by digestive system tumors, and the incidence and mortality rate of main digestive system tumors including esophageal cancer (ESCA), GC, colorectal cancer (CRC), as well as hepatocellular, gallbladder and pancreatic cancer (PC) are listed in Table 1.

Esophageal squamous cell carcinoma (ESCC) is the most frequent ESCA subtype internationally. In general, the genetic alterations of PIK3CA (24%), and PTEN (7%) are observed in ESCA (Table 1), especially the somatic mutations of PIK3CA (7.2% vs 12.5%), PIK3C2A (0.7% vs. 0), PIK3CG (2.9% vs. 4.2%) and PIK3C2G (0 vs. 37.5%) are observed respectively in 139 paired ESCC cases and 24 cell lines [98]. Even more, PIK3CA mutations are frequent in ESCC associated with chagasic megaesophagus and are associated with a worse patient outcome [99]. HERG1, LSD1, CEP55, CACNA2D3, CircVRK1 and lncRNA GAS5 affect the proliferation, migration, invasion or radioresistance of ESCC cells via the PI3K/AKT pathway [100,101,102,103,104,105]. After all, a limited number of clinical trials of PI3K inhibitors BYL719 and BKM120 in ESCC patients may bring efficacious therapeutic proposals (Table 2).

The incidence (5.7%) of GC, in which gastric adenocarcinoma (GAC) is the dominant subtype, has continued to decline worldwide due to the H pylori treatment [106], but the mortality rate (8.2%) remains the second most common cause of cancer death worldwide (Table 1). As shown in Table 1, the overall genetic alterations of PI3K/AKT pathway are observed with PIK3CA (17%) and PTEN (11%) in GC. But one research reveals that PI3K/AKT pathway genetic mutations are found in 69 (16%) of the 431 GC patients including PIK3CA (13.2%) and PTEN (4.0%), as well as PIK3CA amplifications are found in 206 (47.8%) of the patients [107]. Another research shows that advanced GC patient have more frequency of PIK3CA mutations in codon 545 than in codon 1047 [108]. A large number of researches confirm that besides NETO2, UFM1, STIL, LEMD1, SPP1 and PRL-3, miR-19a, 21, 34a, 137 and 196b, as well as lncRNA MALAT1, STXBP5-AS1 and PICART1 are involved in modulating biological functions of GC cells via PI3K/AKT pathway [109,110,111,112,113,114,115,116,117,118,119,120,121,122]. A lot of clinical trials of PI3K inhibitors (BKM120, BYL719 and GSK2636771. Table 2) and AKT inhibitors (MK2206, GSK2110183 and GDC-0068. Table 3) in GC patients try to save their lives, especially the patients with advanced or metastatic GC.

Although CRC screening has reduced the incidence and mortality nowadays [123], CRC remains one of the main reasons of tumor-related deaths worldwide (Table 1). The overall genetic alterations of PI3K/AKT pathway in CRC are observed as follows: PIK3CA (22%), PIK3R1 (5%), PIK3R2 (2.2%), AKT1 (1.8%), AKT2 (2.5%) and PTEN (8%, Table 1). Contrary to predictions, PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC, whereas they are closely associated with KRAS mutations, as well as PIK3CA exon 9 and 20 mutations show different tendencies with respect to BRAF mutation and MSI status [124]. Similar to ADC, the expression of PIK3IP1 is also significantly lower in CRC tissues [67]. CXCL12, NLRC3, Wnt/β-catenin target genes including BAMBI, BOP1, CKS2 and NFIL3, as well as miRNA-135b, Linc00659 and CRNDE are associated with the proliferation, invasion or metastasis of CRC cells via PI3K/AKT signaling [125,126,127,128,129,130]. As shown in Tables 2 and 3, multiple clinical trials of PI3K/AKT inhibitors in CRC patients try to yield useful inhibitors for treatment [131].

As the most common mesenchymal tumor of the digestive system, gastrointestinal stromal tumors (GISTs) mainly harbor mutually exclusive KIT or PDGFRA mutations, which lead to constitutive activation of the encoded receptor tyrosine kinase (RTK) and activation of downstream pathways including PI3K/AKT pathway [132, 133]. Genetic alterations of PIK3CA and PTEN are observed more frequency in malignant GISTs than in less malignant GISTs in 65 GIST samples with 14/65 overall genetic alterations of PI3K/AKT pathway [134]. It is noted that FASN overexpression often occurs in high-risk and metastatic GISTs, whereas combination therapy with imatinib and C75 targeting FASN has been demonstrated in vitro and vivo to down-regulate the phosphorylation levels of the KIT and PI3K/AKT/mTOR pathway [135, 136]. MiR-374b modulates proliferation and apoptosis of GIST cells through PI3K/AKT pathway [137]. Combination of imatinib mesylate (IM) and MK2206 provide obviously greater efficacy than treatment with IM or MK2206 alone in vitro and vivo preclinical study of GIST [138]. Furthermore, clinical trials of combination of Imatinib and BKM120 (NCT01468688) or BYL719 (NCT01735968, Table 2) were tested in GIST patients.

Being the third most common cause of cancer death worldwide with the mortality rate of 8.2%, hepatocellular cancer (HCC) is a distinct tumor of the digestive system and exhibits a different genetic alteration pattern of PI3K/AKT pathway, such as PIK3CA (3%), PIK3R1 (1.2%), PIK3R2 (1.5%), AKT1 (0.7%), AKT2 (1.1%) and PTEN (4%) respectively (Table 1). Similarly, PIK3IP1 also suppresses the development of HCC [67, 139]. Moreover, APLN, miR-7, -367, -1296, and -3691-5p as well as lncRNA PTTG3P and LINC01133 are associated with the proliferation, invasion, metastasis or EMT of HCC cells via PI3K/AKT pathway [140,141,142,143,144,145,146]. A small amount of clinical trials of PI3K inhibitors (SF1126, GSK2636771) and AKT inhibitors (MK2206) in HCC patients may give them an opportunity for relief (Tables 2 and 3).

Regarding gallbladder cancer (GBC) is the most common malignancy of the biliary tract, the general genetic abnormalities of PIK3CA (10%) and PTEN (2.3%) are found (Table 1), especially the PIK3CA E545K mutation rate (6.15%) [147]. Due to ErbB2 and ErbB3 mutations at a frequency of 7–8% in GBC, ErbB2/ErbB3 mutation inducing PD-L1 overexpression can mediate immune escape of tumor cells via PI3K/AKT pathway in vitro [148]. In addition, EIF3d, UBR5, BRD4, TRIM31 and LINC00152 are demonstrated to contribute to cell growth or tumor metastasis of GBC cells via PI3K/AKT pathway [149,150,151,152,153]. Currently, only MK2206 was tested in clinical trials (NCT01859182 and NCT01425879) in GBC patients.

Pancreatic cancer (PC) is a fatal malignancy in the digestive system tumors and takes the first place among asymptomatic cancers (Table 1). Take into consideration that more than 90% of PC is pancreatic ductal adenocarcinoma (PDAC) with the 5-year overall survival (OS) rate less than 5–10% [154], novel targeting therapies are in urgent need. In contrast to the well-known genetically inactivated of P16 (90%), TP53 (75%), DPC4 (55%), as well as activated oncogene KRAS (90%) and Her2 (4–50%) in PDAC [155,156,157,158,159], the overall genetic aberrations of PI3K/AKT members (PIK3CA, 2.3% and PTEN 1.9%, Table 1) are less frequently. Interestingly, pancreatic cell plasticity and cancer initiation induced by Kras is completely dependent on wild-type p110α [160], and PAK4 interacts with p85α can affect the migration of PDAC cells [161]. Significantly, the mutations of PIK3CG in PDAC are also revealed [156]. EG-VEGF, TMEM158, miR-107, as well as LncRNA ABHD11-AS1, SNHG1 and AB209630 are involved in proliferation, apoptosis, metastasis or carcinogenesis of PDAC cells through PI3K/AKT pathway [162,163,164,165,166,167]. Plenty of clinical trials of PI3K inhibitors (BKM120, BYL719, GSK2636771, PKI-587, BEZ235 and LY3023414. Table 2) and AKT inhibitor (MK2206. Table 3) in PDAC patients may reveal promising therapeutic activities.

Abnormalities of the PI3K/AKT pathway in breast and female reproductive system tumor

BC, which is Estrogen (ER)-related cancer, is the second common cancer in the world (morbidity of 11.6%) but in the first place and the most frequent cause of cancer death (mortality of 6.6%) among women worldwide (Table 1). Compared to the recognized genetically diverse of Her2 and TOP2A of BCs, the overall genetic alterations of PI3K/AKT pathway are not uncommon, especially PIK3CA (37%) and PTEN (8%, Table 1). Remarkably, hotspot mutations in PIK3CA are frequent in ER+BCs, which account for up to 80% of BCs, and Her2 mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to anti-ER resistance in ER+BCs. Hence, dual blockade of the Her2 and ER pathways is necessary for the treatment of ER+/Her2 mutant BCs [168]. Moreover, PIK3CA and MAP3K1 alterations reveal Luminal A status in ER+ metastatic BCs and the patients are likely to clinically benefit from BKM120 [169]. On the other hand, top to 70% of patients with breast cancer brain metastases (BCBM) show the activated PI3K pathway [170], and GDC-0084 induces apoptosis of PIK3CA-mutant BCBM cells by suppressing activation of AKT and p70 S6 kinase [171]. Additionally, PRLR/Jak2/STAT5 is the main signaling pathway for activation in mammary gland, and PRLR-triggered pro-tumorigenic pathways in BC include the PI3K/AKT pathway [172]. As well, numerous studies have shown that IRS4, CDK12, SPC24, Mfng, Transgelin 2, STX3, SOX4, PAK4, TPX2, MEG3 and miR-21, -93, -106b, -130b, -214, -361-5p, -489, -511, -564 as well as lncRNA‑HOTAIR and MALAT1 regulate tumorigenesis, proliferation, apoptosis, invasion, migration, paclitaxel resistance or anti-Her2 therapy (trastuzumab) resistance of BC cells through PI3K/AKT pathway [173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191]. And then, PI3K/AKT inhibitors have gained wide attentions, and a large number of clinical trials may have provided tremendous promises in the treatment of BC patients (shown in Tables 2 and 3).

Globally, the incidence and mortality rate of ovarian cancer (OC), which is the most frequently fatal cancer in female reproductive tract with a wide-range of pathological subtypes, are 1.6% and 1.9% respectively (Table 1). Ovarian serous cystadenocarcinoma (OSC), the leading common subtype of epithelial ovarian cancers (EOC) accounting for 90% of OC, harbors overall genetic alterations of PIK3CA (29%), PIK3R1 (5%), PIK3R2 (9%), AKT1 (5%), AKT2 (8%) and PTEN (7%, Table 1) besides the mutant p53 in high-grade OSC (HGOSC), germline BRCA1 and BRCA2 mutations. Furthermore, another subtype of EOC, ovarian clear cell carcinomas (OCCCs), shows more frequently mutations of PIK3CA (33%) and PTEN (5%) in overall 97 OCCC cases, especially mutations of PIK3CA (46%) in the 28 cases of affinity purified OCCCs and OCCC cell lines [192], than the mutation of PIK3CA and PTEN (both < 5%) in HGOSC [193]. Huge amounts of studies have shown YAP, PKG II, SIK2, SERPIND1, miR-15b, -21, -150, -222-3p, -337-3p, -497, -503 and -936, as well as LncRNA MALAT1 and JPX modulate proliferation, apoptosis, invasion, migration, angiogenesis, progression, glucose metabolism or drug resistance of OC cells by PI3K/AKT pathway [194,195,196,197,198,199,200,201,202,203,204,205,206,207]. Some clinical trials of PI3K/AKT inhibitors or in combination with chemotherapy drugs listed in Tables 2 and 3 may help relieve the patients of OC.

Along with recent compelling evidence that OSC actually arises from the epithelial lining of fallopian tube, the true incidence of primary fallopian tube carcinoma (PFTC) has been substantially underestimated, which was previously considered as a rare neoplasm accounting for 0.14–1.8% of genital malignancies [208, 209]. Furthermore, aberrant p53/KRASV12/c-Myc or p53/KRASV12/PI3K/AKT signaling is the minimum requirement for fallopian tube secretory epithelial cells (FTSECs) carcinogenesis [210], and increased copy number of PIK3CA has been observed in six fallopian tube carcinomas (FTCs) [211]. Thus, although the studies of PI3K/AKT signaling in FTC are numbered, there are still several clinical trials of PI3K/AKT inhibitors trying to treat patients with FTCs (Tables 2 and 3).

Cervical cancer (CC) is a prominent example of HPV-related cancer, accounting for 3.2% of all human cancers with the mortality rate of 3.3% (Table 1). A litany of genetic alterations induced by HPVs in CC activate four major upstream pathways (GFR, Notch receptor, RAS isoforms and p110α) to stimulate host cell survival, proliferation and carcinogenesis through the PI3K/AKT/mTOR pathway. Considerable overall genetic alterations of PI3K/AKT pathway in CC have emerged with PIK3CA (39%) and PTEN (13%, Table 1). In particular, the mutations of PIK3CA E542K and E545K promote glycolysis and proliferation of CC in vitro and vivo [212]. NBPF1, ARHGAP17, miR-99b, -181a2/181b2, -338, -383, -433 and -489, as well as LncRNA ANRIL, CRNDE, NEAT1 and LINC01305 are involved in the proliferation, invasion, autophagy or EMT via PI3K/AKT pathway [213,214,215,216,217,218,219,220,221,222,223,224]. Currently, only preclinical trials of PI3K inhibitor LY294002 has revealed it significantly radiosensitized CC cell lines in vitro and vivo [225, 226], and the terminated clinical trials of AKT inhibitor GSK2141795 (NCT01958112, Table 3) has tried to display a novel treatment approach to patients of CC.

Attributed to the global incidence (2.1%) and mortality rate (0.94%) of corpus uteri cancer, which is usually referred to endometrial cancer (EC), EC researches have gained a big momentum in recent years. Particularly, the endometrioid type of EC (EEC) progressing from intraepithelial endometrial neoplasia in a large proportion of cases belongs to ER-related cancer, and is directly associated with inactivation of PTEN. Hereby, the remarkable overall genetic alterations of PI3K/AKT pathway are shown in EC, such as: PIK3CA (34%), PIK3R1 (19%), PIK3R2 (5%), AKT1 (3%) and AKT2 (5%), especially PTEN (32%, Table 1). What’s more, it’s revealed that the majority of the G3 EEC samples have exhibited PIK3CA mutations (39%) and PTEN mutations (67%) [227]. Moreover, JQ1, NEDD4, PDCD4, miR-101, -494-3p, Lnc RNA LINP1 and MEG3 have shown their aptitudes for controlling tumorigenesis, proliferation, apoptosis, invasion, progression of EC cells via PI3K/AKT pathway [228,229,230,231,232,233,234]. Thus, EC patients may get benefit from the mounting clinical trials of PI3K/AKT inhibitors listed in Tables 2 and 3.

Dysregulation of the PI3K/AKT Pathway in the genitourinary system tumors

The morbidity of PCa ranks third in the world (7.1%) since men obtain a small but finite benefit from PCa screening in terms of PCa-specific mortality, which is estimated as 3.8% globally [235] (Table 1). Seeing that loss of function of PTEN, resulting in dysregulated activation of the PI3K signaling network, is recognized as one of the most common driving events in PCa development [236], the overall genetic alterations of PI3K/AKT pathway in PCa have demonstrated with PIK3CA (6%), and visible PTEN (18%, Table 1). Sexual hormones have been historically associated with PCa for the androgen deprivation therapy (ADT), but scientific evidences including the increasingly emerging of castration resistant prostate cancer (CRPC) are inconsistent to decide whether their involvement is aetiological or a phenotype component of the disease. However, similar to BC, PRLR/Jak2/STAT5 is also the main signaling pathway for activation in prostate gland, and PRLR-triggered pro-tumorigenic pathways in PCa include PI3K/AKT [172]. In addition, AEP, SCL/TAL1, SIRT3, Snail, MED15, STIM1, ST6Gal-I, Glyoxalase 2, ASF1B, GPCR48/LGR4, AP4, GCN5, SAG/RBX2 E3, miR-7, -101, -129, -133a-3p, and -4638-5p, as well as LncRNA HCG11 and ATB govern tumorigenesis, progression, metastasis, EMT or castration resistant of PCa cells via PI3K/AKT pathway [237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256]. Preclinical trial of dual BRD4/PI3K inhibitor SF2523 [257] as well as a few of clinical trials of PI3K/AKT inhibitors may develop new therapeutic strategies for PCa patients (Tables 2 and 3).

Kidney cancer (KC) is a malignancy originating in the urinary tubular epithelial system of the renal parenchyma, which mainly means renal cell carcinoma (RCC). Accompanying with the recent hunt for the genetics causes of KC, such as TFE3, TFEB, or MITF gene fusions, the overall genetic alterations of PI3K/AKT pathway comprising PIK3CA (2.8%), PIK3R1 (0.4%), PIK3R2 (0.3%), AKT1 (0.5%), AKT2 (0.6%) and PTEN (4%, Table 1) are captured in KC. To a further extent, PI3K/AKT/mTOR is identified as a highly enriched pathway in translocation RCC with TFE3 fusion (TFE3-tRCC) by miRNA microarray analysis [258]. Besides that PIK3R1 regulates EMT and stem-like phenotype of RCC cells through the AKT/GSK3β/CTNNB1 pathway [259], FoxO, PKCε, TPD52, NOTCH1, ETS2, miR-19b, -122, -182, -193a-3p, -195, and -224, as well as LncRNA MALAT1, TP73-AS1 and HOTTIP modulate proliferation, apoptosis, invasion, metastasis, or EMT via PI3K/AKT pathway [260,261,262,263,264,265,266,267,268,269,270,271,272]. However, only a few of clinical trials of PI3K/AKT inhibitors in touch try to offer hope for KC patients (Tables 2 and 3).

Bladder cancer (BLCA) is complex disease mainly consisting of non-muscle-invasive bladder cancer (NMIBC, about 70%), and muscle-invasive and metastatic bladder cancer (MIBC, about 30%). Indeed, PIK3CA mutations are considered as an early genetic alteration associated with FGFR3 mutations in superficial papillary NMIBC [273] and the activation of the PI3K/AKT pathway is identified to induce urothelial carcinoma of the renal pelvis [274]. And the overall genetic alterations of PIK3CA (24%) are described in BLCA (Table 1). It is further shown that PPARγ, Sema4D, CCDC34, miR-29c, -143, -145 and -294, as well as LncRNA ATB, LINC00641, HULC, DUXAP10 and UCA1 regulate proliferation, migration, or invasion of BLCA cells via PI3K/AKT pathway [275,276,277,278,279,280,281,282,283,284,285]. Even though there is a significant unmet need for new therapies, however, at present only a small amount of clinical trials of BKM120 and GSK2636771 try to find out what PI3K inhibitor’s prospects bring to the BLCA patients (Table 2).

Testicular cancer (Te Ca) is the most common malignancy among men between 14 and 44 years in the world. Testicular germ cell tumors (TGCTs) are classified as seminoma and non-seminoma. Among the numerous genetic and environmental factors, cryptorchidism is the most common risk factor. Compared to the noted KRAS and NRAS mutations in TGCTs [286], the overall genetic alterations frequency of PIK3CA (3%), PIK3R1 (1.3%), AKT1 (0.7%) and PTEN (0.7%) are much less, even though mutations in PIK3CA and AKT1 are observed exclusively in cisplatin-resistant TGCTs [287]. AXIN1, TDRG1 and LncRNA H19 regulate cell viability, apoptosis or cisplatin resistance via the PI3K/AKT/mTOR signaling pathway [288,289,290]. Unfortunately, PI3K/AKT inhibitors have not yet applied in clinical trials of TGCT patients up to now.

Description of the PI3K/AKT pathway in the hemato-immune system tumors

Hematologic cancers are associated with hemato-immune system, which comprise lymphomas, myelomas and leukemias. Lymphoma, which is classified with Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), and multiple myeloma (MM) emanate from the cells of the immune system, while leukemia originates from blood-forming tissues such as the bone marrow [291, 292].

HL is a rare B-cell malignant neoplasm approximately accounting for 0.44% of all new cancers annually, which is classified into two discrete disease entities: classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). With four subgroups including nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte depletion (LDCHL), and lymphocyte-rich (LRCHL), CHL is relatively less known about genetic lesions owing to the fact that the neoplastic Hodgkin- and Reed-Sternberg (HRS) cells constituting only a small proportion of the tumor tissue [293]. But the prevalence of EBV in HRS cells varies according to the histological subtype and epidemiologic factors from highest frequency in MCCHL to the lowest in NSCHL, and EBV-encoded LMP1 utilizes the PI3K/AKT/mTOR signaling axis to induce ectopic CD137 expression in HRS cells, which results in enhancing the proliferation rate of HRS cells [294, 295]. Furthermore, differences related to EBV status or histological subtypes are observed for PI3K signaling in pediatric HL patients by using hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA), where MCCHL and EBV+ cases were less frequently affected by mutations in ITPKB and GNA13 genes [296]. Recent evidences revealing that germinal center B-cells (GCB cells) are the cellular origin of HRS cells [294], and the facts that PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in both activated B cell-like (ABC) and GCB cells of diffuse large B cell lymphoma (DLBCL) [297] suggest that PI3K/AKT may promote lymphomagenesis of GCB cells in HL, which is a remarkable coincidence with the other evidences that the PI3K/AKT pathway plays a pathogenetic role in HL [298, 299]. Thus, novel therapeutic options targeted PI3K/AKT pathway promote apoptosis or cell death, as well as regulate tumor microenvironment (TME) of HL cells in preclinical studies [300,301,302], and patients may get beneficial strategy in clinical trials of PI3K/AKT inhibitors (Tables 2 and 3).

As the most common malignancies of hemato-immune system in the world, NHL represents a wide spectrum of illnesses that vary from the most indolent to the most aggressive malignancies, which encompasses 2 main type: mature B-cell neoplasms (B-NHL, 85–90%) and mature T-cell and natural killer (NK)-cell neoplasms (T/NK-NHL, 10–15%; 2016 WHO). Indolent B-cell lymphomas (iB-NHL) represents 35–40% of NHL, and the most common subtypes include follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a fraction of mantle cell lymphoma (MCL) cases, extramedullary, nodal and splenic marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL). On the other hand, the most common subtypes of aggressive B-NHL are large B-cell lymphomas, which is composed of DLBCL, not otherwise specified (NOS, 80%) and additional 13 specific variants of DLBCL (20%) including anaplastic (ALK + LBCL) and primary mediastinal lymphoma (PMLBCL), and other various kinds of DLBCL [303,304,305,306]. Anyway, the overall genetic alterations of PIK3CA (0.4%), PIK3R1 (0.5%), PIK3R2 (0.1%), AKT1 (0.1%), AKT2 (0.1%) and PTEN (1.1%, Table 1) are observed statistically in NHL.

Apparently, two specific lymphomas, FL and DLBCL, account for about 65% of all NHL, and more importantly, the genomic profile of transformed FL shares similarities with that of GCB de novo DLBCL, and thus a thorough knowledge of these two entities related with PI3K/AKT pathway is essential [307,308,309]. Despite the recognized fact that overwhelming majority of FL cases have the characteristic (14;18) translocation involving the IgH/bcl-2 genes, while B-cells "arrested" in germinal centers of FL acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT pathway, and so on [310, 311]. Especially, the facts that deletion of PIK3CD results in decreased number of marginal zone (MZ) B cells and pleural/peritoneal cavities in mice, as well as the evidences that PIK3CD-depleted B cells also fail to proliferate in vitro in response to BCR or CD40 signals and have impaired both humoral T-cell-dependent and T-cell-independent responses suggest that p110δ plays a critical role in B cell homeostasis and function [312,313,314]. Consequently, following with the world's first selective PI3Kδ inhibitor CAL-101 was approved by the FDA for the treatment of FL, CLL and SLL in 2014 [315] [NCT01282424, NCT02136511], the PI3K/AKT inhibitors have shown remarkable activity in an increasing subset of patients with NHL [316] (Tables 2, 3). Copanlisib (BAY 80-6946) and Duvelisib (IPI-145) are newly approved PI3K inhibitors that offer objective, although relatively short-lasting, responses in patients with heavily pre-treated FL and other NHL, and more such targeted agents may be approved soon [307, 317,318,319,320] (Tables 2 and 3).

As aforementioned, DLBCL is a highly aggressive heterogeneous disease with two subtypes: GCB and ABC [297]. One study shows that deregulation of the PI3K/AKT pathway by the inactivation of PTEN are found in 55% of GCB-DLBCL cases, but only in 14% of non-GCB-DLBCL and worsens prognosis in 248 primary DLBCL patients [308]. Another study finds the PIK3CA amplification of 12.7% and PTEN loss of 12.2% in DLBCL [321]. Furthermore, upregulation of PRMT5 and CXCR4 are involved in lymphomagenesis or resistance mechanism via the PI3K/AKT pathway in DLBCL cells [297, 322]. Preclinical trial of BAY80-6946 in DLBCL cells [323] and the clinical trials of BAY80-6946, INCB050465, CUDC-907 and MK2206 in patients with DLBCL have improved our ability to manage patients with this disorder (Table 2).

T/NK-NHL is a heterogeneous group of malignancies often associated with poor clinical outcomes, and each malignancy within this group is characterized by unique clinicopathologic features, while T cell receptor/NF/kB (TCR/NF/kB) signaling highly enriched and dysregulation of JAK/STAT pathway, specifically aberrant STAT3 activation, are the common feature among these lymphomas [324,325,326]. A study with 426 adult T cell leukemia/lymphoma (ATL) cases associated with human T cell leukemia virus type-1 (HTLV-1) infection shows that PI3KCD mutation is also observed in 9 of 370 (2.4%) cases besides the highly enriched for TCR/NF/kB signaling, T cell trafficking and other T cell-related pathways [324]. In addition, the alterations of PI3K signaling are involved in the multilobulated nucleus formation and cell proliferation in ATL cells [327]. Therefore, preclinical trial of CAL-101 inducing apoptosis in ATL cells [328] and a series of clinical trials of PI3K/AKT inhibitors are expected to offer new treatment regimens for patients with T/NK-NHL [316] (Tables 2, 3).

MM accounts for 0.88% of all cancers with the mortality rate (1.1%). Almost all MM patients evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). Despite that hotspot mutations of PIK3CA (E542K, E545K and H1047R) and AKT1 genes (E17K) are absent in MM [329], the R310C mutation of PIK3CA gene [330] is identified in some cases of MM, as well as ROR2 drives the interaction of MM cells with TME through AKT activation [331]. Furthermore, only the blockade of PIK3CA is sufficient to induce cell death in a sizeable subgroup of MM samples, and PIK3CA inhibitor BYL-719 in combination treatments with other compounds establishes anti-myeloma agents resulted in strongly enhanced MM cell death [332]. Therefore, some preclinical studies have examined PI3K/AKT pathway inhibitors in MM, such as TAS-117, PI-103 and BEZ235 [333,334,335]. Fortunately, some of the clinical trials of PI3K/AKT inhibitors have demonstrated encouraging clinical activity in relapsed and relapsed/refractory (R/R) MM [336,337,338,339] (NCT01002248; NCT01476137; NCT00881946) (Tables 2 and 3).

The definition of leukemia is increasingly employed that an aberrant hyper-proliferation of immature blood cells either of the myeloid or lymphoid lineages forms liquid cancer, which is classified with acute or chronic. With morbidity (2.4%) and mortality rate (3.2%) across the world (Table 1), leukemia is a series of life-threatening malignant diseases, particularly in the adolescent and young adult (AYA) population, in which the acute leukemias are most prevalent [340]. Apart from the iconic BCR/ABL oncogene formation in chronic myeloid leukemia (CML) and the genetic abnormalities frequently linked to treatment resistance and poor patient outcome in acute myeloid leukemia (AML), for example the unique PML-RARA fusion in acute promyelocytic leukaemia (APL; AML M3), the PI3K/AKT pathway can function as a prosurvival factor in leukemia stem cells and early committed leukemic precursors with the following facts: Firstly, the overall genetic alterations of PIK3CA (0.6%), PIK3R1 (0.6%), PIK3R2 (0.4%), AKT1 (0.5%), AKT2 (0.1%) and PTEN (0.7%, Table 1) are observed in leukemia (Table 1). Secondly, PTEN plays critical roles in regulating not only hematopoietic stem cell activity through a Niche-dependent mechanism, but also hematopoiesis and leukemogenesis [341,342,343]. Furthermore, TAL1, c-Jun, EZH2, TRIM22, ETV6/RUNX1, miR-7, -22, -26b, -103, -125b, -126, -139-5p, -181c, -193a, -628, and -3142, as well as LncRNA HULC, UCA1, linc00239 and LINC00265 control leukemogenesis, proliferation, apoptosis or chemoresistance via PI3K/AKT pathway [344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363]. Hereafter, PI3K/AKT pathway inhibition is regarded as a therapeutic approach [364, 365] followed by the preclinical studies in leukemia cells [366, 367] in spite of the upregulated expression of P2RY14 in acute leukemia cells resistant to PI3K/mTOR inhibition [368]. Since CAL-101 has been approved for marketing in patients with CLL/SLL, the clinical trials of PI3K/AKT inhibitors such as: BAY80-6946, KM120, YY-20394, BEZ235, PKI-587, IPI-145, CAL-101, TGR-1202, MK2206 and GSK2141795 try to seek new therapeutic approach in relapse or refractory patients with CLL or newly diagnosed AML and acute lymphocytic leukemia (ALL, Tables 2 and 3).

Featuring the PI3K/AKT pathway in the bone and soft tissue tumors

Osteosarcoma (OS) is the most frequent primary solid malignancy of bone with the presence of malignant mesenchymal cells which produce osteoid and/or immature bone. The incidence of OS is higher in adolescence (8–11/million/year) than in the general population (2–3/million/year), and > 90% of OS patients died from pulmonary metastases before polychemotherapy. Although the biological and genetic studies of OS have made substantial progress, there has been no qualitative breakthrough in treatment over the past 30 years. Besides the alterations of TP53, RB1, ATRX and DLG2 in OS, total genetic alterations in the PI3K/AKT/mTOR pathway are observed in 14 of 59 (24%) OS patients, and PIK3CA and mTOR are vital for the proliferation and survival of OS cells [369] (Table 1). Furthermore, dual PI3K/mTOR inhibitors are effective at inducing apoptosis in primary OS cell cultures in vitro in both human and mouse OS, while specific PI3K or mTOR inhibitors are not effective [370], which is consistent with the preclinical study’s result that BEZ235 inhibits proliferation and tumor development of OS cells in vivo [371].

Ewing's sarcoma (EWS), the second most common bone tumor in children and adolescents, is identified by the characteristic t (11;22) chromosomal translocation and resulting oncogenic EWS–FLI1 fusion, for which no cure is currently available. Overall genetic alterations of the PI3K/AKT pathway are observed in EWS cases with PIK3CA (1.4%), PIK3R1 (0.5%) and PTEN (0.5%, Table 1), which play an important role in EWS pathogenesis [372]. Moreover, SOX2, Ski, miR-30d and -185 regulate proliferation, apoptosis, migration or progression of EWS cells though PI3K/AKT pathway [373,374,375,376]. In addition, hnRNPM motifs are significantly enriched under the inhibition of the PI3K/AKT/mTOR pathway by BEZ235 in EWS cells. On the other hand, hnRNPM down-expression revokes the BEZ235-induced splicing changes including hnRNPM binding sites, enhanced BEZ235 cytotoxicity and limited the clonogenicity of EWS cells [377].

Currently, pediatric patients of OS or EWS may be beneficial from the ongoing clinical trials of BAY80-6946 (NCT03458728) and LY3023414 (NCT03213678, Table 2).

The trait of the PI3K/AKT pathway in skin cancer

Skin cancer is the most common carcinoma, affecting millions worldwide annually, which generally divided into malignant melanoma and non-melanoma skin cancer. Cutaneous melanoma ranks 20th among most common cancers worldwide and rapidly becomes life-threatening once it has spread. Even though solar ultraviolet exposure is the main environmental risk factor for cutaneous melanoma development, there are still genetic susceptibility factors, such as germline mutations in p16 or CDK4, and genesis of melanoma, such as the main genetic drivers BRAF, NF1 and NRAS mutations [378, 379]. Since BRAFV600E-mutated melanomagenesis is often accompanied by silencing of PTEN [380], the increasing genetic alterations in PI3K/AKT pathway have been observed in melanoma including: PIK3CA (5%) and PTEN (12%, Table 1). Notably, dysfunction mutations of NF1 induce BRAF inhibitor resistance by activating RAS and its downstreams including both MAPK and PI3K/AKT/mTOR pathways in cutaneous melanoma [381, 382]. Even more, the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma can be forestalled by PI3K blockade [383]. Other than that, ROR1, FOXC1, MIF, TGFβ, lncRNA SNHG17, MIAT, MHENCR, OR3A4 and H19 regulate proliferation, progression, migration, invasion, metastasis or EMT-like transition though PI3K/AKT pathway in melanoma cells [384,385,386,387,388,389,390,391,392]. And now, a limited number of clinical trials of PI3K/AKT pathway inhibitors (BKM120, PX-866, GSK2636771, GSK2141795 and MK2206) try to find new ways other than current classic RAF/MEK/MAPK pathway inhibitors to treat the patients with metastatic or advanced melanomas (Tables 2 and 3).

Points of dispute or unanswered questions

In general, ATC, NSCLC, EC, GC, CRC, BC, OC, CC, EC and BLCA exhibit higher frequencies of PIK3CA mutations than other tumors, while PTEN mutations are predominantly found in GBM, EC and PCa (Fig. 1, Table 1). No matter what kind of the genetic alteration happens in PI3K/AKT pathway, or the factor influences cellular behaviors via PI3K/AKT pathway, it leads to the hyper-activation of PI3K/AKT pathway. Growing evidences have shown that the hyper-activation of PI3K/AKT pathway in malignant tumor influences the tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, EMT, stem-like phenotype, immune microenvironment, drug resistance of tumor cells (Fig. 1). Interestingly, some protein may play a dual role in PI3K/AKT pathway. For instance, unlike the previous understanding that INPP4B is a negative regulator of PI3K/AKT pathway in TC cells in vivo [49], the tumor-promoting features of INPP4B have yet been observed in leukemia and BC [393,394,395]. Why and how the INPP4B is a double-edged sword in PI3K/AKT pathway is still a puzzle and it needs further research to evaluate the evidences.

Potential research/future

More and more promising PI3K/AKT pathway inhibitors seem to be useful to overcome malignant tumor, especially CAL-101 treated in patients with hemato-immune system tumors has achieved exhilarating results. Obviously, CAL-101 not only causes a rapid and sustained reduction in lymphadenopathy, but also regulates the immune environment in CLL [396, 397]. However, things are more complicated than our envisage and there is always coexist with abnormal activity of other pathways interacted with PI3K/AKT pathway in tumors. For example, AKT inhibition induces the expression and phosphorylation of multiple RTKs, and the activated RTK signaling may attenuate their antitumor activity in BC cells, which suggest that combined inhibition of AKT and HER kinase activity is more effective than either alone [398]. There are some other embarrassments findings that small molecule PI3K/AKT pathway inhibitors could promote the (re)phosphorylation of AKT2 which is linked to the redistribution and adaptive reprogramming of mitochondria, contributing to drug resistance and metastasis in GBM cells [399, 400]. Thence, novel combination therapies that target mitochondrial adaptation and PI3K pathway may achieve better efficacies than either alone in the clinic.

Collectively, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the promise of the novel inhibitors to the patients for targeted therapies.

Fig. 1
figure 1

Overview of the PI3K/AKT signaling cascades in cancers

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