Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial–mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.


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. 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)P 2 ) with phosphorylation at the D3 position of the inositol ring to the second messenger phosphatidylinositol 3,4,5-triphosphate (PIP 3 ). Two PIP 3 -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)P 3 and PI(3,4)P 2 (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 PIP 3 generated by PI3K back to PIP 2 . 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 PIP 2 [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 ATPcompetitive 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. 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 ://clini caltr ials.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].
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.cbiop ortal .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 . 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    To assess the safety, tolerability, and PO of pictilisib administered with letrozole or IV paclitaxel with and without IV bevacizumab or IV trastuzumab in participants with locally recurrent or metastatic BC I NCT00960960 Determining the MTD, safety and effectiveness of BYL719 combined with Nab-Paclitaxel in treating patients with HER2-BC, along with the determination of how long this drug combination will keep the disease from getting worse I/II NCT02379247 A Study of BYL719 in combination with paclitaxel in advanced solid tumors followed by two expansion phases in locally chemotherapy naive HER2-MBC patients and in recurrent and metastatic HNSCC patients pre-treated with platinum-based therapy I NCT02051751 To determine whether treatment with BYL719 plus letrozole led to an increase in pathologic clinical response and ORR compared to treatment with placebo plus letrozole in patients with BC

II NCT01923168
To assess the MTD and/or the RP2D(s), safety, tolerability, the single and multiple dose PK profile and the preliminary anti-tumor activity of BYL719 and BKM120 in combination with tamoxifen plus goserelin acetate in premenopausal advanced HR + BC patients I NCT02058381 To describe safety and tolerability of the BYL719 and everolimus or BYL719, everolimus and exemestane combinations I NCT02077933 Published data support the hypothesis that a PF-04691502 in combination with letrozole might mitigate the intrinsic or acquired resistance to hormonal therapy and restore hormone sensitivity in high risk patient population of hormone-sensitive BCs I NCT01430585       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%),  [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). 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].
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.
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.
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 Hodgkinand 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).
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-cellindependent 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).

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].
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 BRAF V600E -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 hyperactivation 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, Fig. 1 Overview of the PI3K/AKT signaling cascades in cancers 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.