Skip to main content
SpringerLink
Log in

PI3K-Akt-mTOR Signaling in Cancer and Cancer Therapeutics

  • Chapter
  • First Online:
PI3K-mTOR in Cancer and Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 992 Accesses

Abstract

The PI3K-Akt-mTOR pathway canonically transduces intracellular signals initiated by insulin binding to its cognate receptor tyrosine kinase (RTK), thereby integrating the sensing of systemic nutrient availability with the regulation of cellular metabolism, growth, and proliferation. As a result of the large-scale sequencing and analysis of human cancer genomes, the PI3K-Akt-mTOR signaling pathway is now also well appreciated to be commonly dysregulated in cancers arising from diverse tissues of origin. Somatic genetic changes have been identified in PIK3CA, PTEN, Akt1, mTOR, and other genes, many of which are known to play important functional roles in cancer cell proliferation and survival. The ubiquity of PI3K-Akt-mTOR pathway activation in cancer has prompted significant interest in the development of small molecule inhibitors of various components of the signaling pathway. Multiple compounds are presently being evaluated in human clinical trials and may enter the armamentarium of standard cancer treatments in the future. Those studies completed to date have highlighted a number of key challenges that will need to be overcome to realize the full potential of targeting the PI3K-Akt-mTOR signaling pathway for clinical benefit. To improve the therapeutic window for PI3K pathway inhibition, compounds that preferentially target the mutant protein may be required. Second, the identification of improved response biomarkers will be needed to facilitate precision trials that aim to enroll only the patients who are most likely to respond to therapy. Third, a comprehensive understanding of the most common mechanisms that promote recovery of signaling activity during drug treatment may provide important leads for new therapeutic combinations. Lastly, strategies for co-drugging may also arise from an improved understanding of how inhibition of PI3K signaling—even when cell cycle arrest and/or apoptosis are insufficient for clinical benefit—creates new vulnerabilities that may be exploited by other available therapies. Such studies will provide a robust preclinical foundation for clinical trials of rational combinations of PI3K-directed therapies with other targeted agents, cytotoxic chemotherapy or immunotherapy that aim to boost clinical response rates, improve treatment durability, and offer cures to greater numbers of patients suffering from cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Averous J, Fonseca B, Proud C (2007) Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene 27:1106–1113

    Google Scholar 

  2. Bader A, Kang S, Vogt P (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103:1475–1479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bar-Peled L, Chantranupong L, Cherniack A, Chen W, Ottina K, Grabiner B, Spear E, Carter S, Meyerson M, Sabatini D (2013) A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science (New York, N.Y.) 340:1100–1106

    Article  CAS  Google Scholar 

  4. Baselga J (2001) Phase I and II clinical trials of trastuzumab. Ann Oncol 12(Suppl 1):S49–S55

    Google Scholar 

  5. Bauer D, Hatzivassiliou G, Zhao F, Andreadis C, Thompson C (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24:6314–6322

    Article  CAS  PubMed  Google Scholar 

  6. Bellacosa A, Testa J, Staal S, Tsichlis P (1991) A retroviral oncogene, Akt, encoding a serine-threonine kinase containing an SH2-like region. Science (New York, N.Y.) 254:274–277

    Google Scholar 

  7. Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, Demanse D, De Buck SS, Ru QC, Peters M et al (2012) Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 30:282–290

    Article  CAS  Google Scholar 

  8. Berenjeno I, Guillermet-Guibert J, Pearce W, Gray A, Fleming S, Vanhaesebroeck B (2012) Both p110α and p110β isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor. Biochem J 442:151–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Berns K, Horlings H, Hennessy B, Madiredjo M, Hijmans EM, Beelen K, Linn S, Gonzalez-Angulo A, Stemke-Hale K, Hauptmann M et al (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402

    Google Scholar 

  10. Bosch, Li, Bergamaschi, Ellis (2015) PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer. Sci Transl Med 7:283ra51

    Google Scholar 

  11. Bouchard C, Lee S, Paulus-Hock V, Loddenkemper C, Eilers M, Schmitt C (2007) FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev 21:2775–2787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brognard J, Sierecki E, Gao T, Newton A (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 25:917–931

    Article  CAS  PubMed  Google Scholar 

  13. Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L, Anderson M, Arden K, Blenis J, Greenberg M (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Google Scholar 

  14. Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D, Frangioni J, Dalal S, DeCaprio J, Greenberg M, Yaffe M (2002) 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol 156:817–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bunney T, Katan M (2010) Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat Rev Cancer 10:342–352

    Article  CAS  PubMed  Google Scholar 

  16. Cardone M, Roy N, Stennicke H, Salvesen G, Franke T, Stanbridge E, Frisch S, Reed J (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science (New York, N.Y.) 282:1318–1321

    Google Scholar 

  17. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki A, Thomas G, Kozma S et al (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Investig 118:3065–3074

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Carver B, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora V, Le C, Koutcher J, Scher H et al (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19:575–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chakrabarty A, Sánchez V, Kuba M, Rinehart C, Arteaga C (2012) Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci USA 109:2718–2723

    Article  CAS  PubMed  Google Scholar 

  20. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder P, Baselga J, Rosen N (2011) Akt inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19:58–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Clarke P, Workman P (2012) Phosphatidylinositide-3-kinase inhibitors: addressing questions of isoform selectivity and pharmacodynamic/predictive biomarkers in early clinical trials. J Clin Oncol Official J Am Soc Clin Oncol 30:331–333

    Article  CAS  Google Scholar 

  22. Costa C, Ebi H, Martini M, Beausoleil S, Faber A, Jakubik C, Huang A, Wang Y, Nishtala M, Hall B et al (2015) Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. Cancer Cell 27:97–108

    Article  CAS  PubMed  Google Scholar 

  23. Crino P, Nathanson K, Henske E (2006) The tuberous sclerosis complex. N Engl J Med 355:1345–1356

    Article  CAS  PubMed  Google Scholar 

  24. Cross D, Alessi D, Cohen P, Andjelkovich M, Hemmings B (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    Google Scholar 

  25. Crowder R, Phommaly C, Tao Y, Hoog J, Luo J, Perou C, Parker J, Miller M, Huntsman D, Lin L et al (2009) PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res 69:3955–3962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Datta S, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg M (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Google Scholar 

  27. De P, Sun Y, Carlson J, Friedman L, Leyland-Jones B, Dey N (2014) Doubling down on the PI3K-Akt-mTOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness. Neoplasia (New York, N.Y.) 16:43–72

    Google Scholar 

  28. Deberardinis R, Lum J, Thompson C (2006) Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J Biol Chem 281:37372–37380

    Article  CAS  PubMed  Google Scholar 

  29. Dentin R, Liu Y, Koo S, Hedrick S, Vargas T (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449:366–369

    Google Scholar 

  30. Deprez J, Vertommen D, Alessi D, Hue L, Rider M (1997) Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem 272:17269–17275

    Google Scholar 

  31. Dibble C, Manning B (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15:555–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R, Tzivion G (2011) Bimodal regulation of FoxO3 by Akt and 14-3-3. Biochim Biophys Acta 1813:1453–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Eijkelenboom A, Burgering B (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97

    Article  CAS  PubMed  Google Scholar 

  34. Elkabets M, Vora S, Juric D, Morse N, Mino-Kenudson M, Muranen T, Tao J, Campos A, Rodon J, Ibrahim Y et al (2013) mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med 5:196ra99

    Google Scholar 

  35. Eser S, Reiff N, Messer M, Seidler B, Gottschalk K, Dobler M, Hieber M, Arbeiter A, Klein S, Kong B et al (2013) Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23:406–420

    Article  CAS  PubMed  Google Scholar 

  36. Fedele C, Ooms L, Ho M, Vieusseux J, O’Toole S, Millar E, Lopez-Knowles E, Sriratana A, Gurung R, Baglietto L et al (2010) Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci USA 107:22231–22236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Feldman M, Apsel B, Uotila A, Loewith R, Knight Z, Ruggero D, Shokat K (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38

    Google Scholar 

  38. Fingar D, Richardson C, Tee A, Cheatham L, Tsou C, Blenis J (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24:200–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fruman D, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13:140–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fu Z, Tindall D (2008) FOXOs, cancer and regulation of apoptosis. Oncogene 27:2312–2319

    Google Scholar 

  41. Gingras A, Kennedy S, O’Leary M, Sonenberg N, Hay N (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12:502–513

    Google Scholar 

  42. Gupta S, Ramjaun A, Haiko P, Wang Y, Warne P, Nicke B, Nye E, Stamp G, Alitalo K, Downward J (2007) Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129:957–968

    Article  CAS  PubMed  Google Scholar 

  43. Harrington L, Findlay G, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie N, Cheng S, Shepherd P et al (2004) The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166:213–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hobert J, Eng C (2009) PTEN hamartoma tumor syndrome: an overview. Genet Med Official J Am Coll Med Genet 11:687–694

    Article  CAS  Google Scholar 

  45. Hortobagyi G, Chen D, Piccart M,  Rugo H, Burris H, Pritchard K, Campone M, Noguchi S, Perez A, Deleu I, Shtivelband M, Masuda N, Dakhil S, Anderson I, Robinson D, He W, Garg A, McDonald E, Bitter H, Huang A, Taran T, Bachelot T, Lebrun F, Lebwohl D, Baselga J (2015) Correlative analysis of genetic alterations and everolimus benefit in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from BOLERO-2. J Clin Oncol 34:419–426

    Google Scholar 

  46. Hresko R, Mueckler M (2005) mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280:40406–40416

    Article  CAS  PubMed  Google Scholar 

  47. Hsu P, Kang S, Rameseder J, Zhang Y, Ottina K, Lim D, Peterson T, Choi Y, Gray N, Yaffe M et al (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science (New York, N.Y.) 332:1317–1322

    Article  CAS  Google Scholar 

  48. Hu H, Juvekar A, Lyssiotis CA, Lien EC, Albeck JG, Oh D, Varma G, Hung YP, Ullas S, Lauring J et al (2016) Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 164:433–446

    Article  CAS  PubMed  Google Scholar 

  49. Ibrahim Y, García-García C, Serra V, He L, Torres-Lockhart K, Prat A, Anton P, Cozar P, Guzmán M, Grueso J et al (2012) PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov 2:1036–1047

    Article  CAS  PubMed  Google Scholar 

  50. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung S, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137

    Article  CAS  PubMed  Google Scholar 

  51. Janku F, Wheler J, Westin S, Moulder S, Naing A, Tsimberidou A, Fu S, Falchook G, Hong D, Garrido-Laguna I et al (2012) PI3K/Akt/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol Official J Am Soc Clin Oncol 30:777–782

    Article  CAS  Google Scholar 

  52. Jansen, Mirzaa, Ishak, O’Roak, Hiatt (2015) PI3K/Akt pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138:613–628

    Google Scholar 

  53. Jewell J, Kim Y, Russell R, Yu F-X, Park H, Plouffe S, Tagliabracci V, Guan K-L (2015) Differential regulation of mTORC1 by leucine and glutamine. Science 347:194–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jung C, Ro S, Cao J, Otto N, Kim D (2010) mTOR regulation of autophagy. FEBS Lett 584:1287–1295

    Google Scholar 

  55. Juvekar A, Burga L, Hu H, Lunsford E, Ibrahim Y, Balmañà J, Rajendran A, Papa A, Spencer K, Lyssiotis C et al (2012) Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov 2:1048–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kang S, Denley A, Vanhaesebroeck B, Vogt P (2006) Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase. Proc Natl Acad Sci USA 103:1289–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kannan A, Lin Z, Shao Q, Zhao S, Fang B, Moreno M, Vural E, Stack B, Suen J, Kannan K, Gao L (2015) Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth. Oncotarget (epub ahead of print)

    Google Scholar 

  58. Kimbung S, Biskup E, Johansson I, Aaltonen K, Ottosson-Wadlund A, Gruvberger-Saal S, Cunliffe H, Fadeel B, Loman N, Berglund P et al (2012) Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition. Cancer Lett 319:232–241

    Article  CAS  PubMed  Google Scholar 

  59. Koo J, Yue P, Gal A, Khuri F, Sun S-Y (2014) Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth. Cancer Res 74:2555–2568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Koo J, Yue P, Deng X, Khuri F, Sun S-Y (2015) mTOR complex 2 stabilizes Mcl-1 protein by suppressing its glycogen synthase kinase 3-dependent and SCF-FBXW7-mediated degradation. Mol Cell Biol 35:2344–2355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, Mulliken JB, Bowen ME, Yamamoto GL, Kozakewich HP et al (2012) Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 90:1108–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Laplante M, Sabatini D (2012) mTOR signaling in growth control and disease. Cell 149:274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee J, Huynh M, Silhavy J, Kim S, Dixon-Salazar T, Heiberg A, Scott E, Bafna V, Hill K, Collazo A, Funari V, Russ C, Gabriel S, Mathern G, Gleeson J (2012) De novo somatic mutations in components of the PI3K-Akt3-mTOR pathway cause hemimegalencephaly. Nat Genet 44:941–945

    Google Scholar 

  64. Liang J, Slingerland J (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle (Georgetown, Tex.) 2:339–345

    Google Scholar 

  65. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor M, Han K, Lee J-H, Ciarallo S, Catzavelos C, Beniston R et al (2002) PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8:1153–1160

    Article  CAS  PubMed  Google Scholar 

  66. Lindhurst M, Sapp J, Teer J, Johnston J, Finn E, Peters K, Turner J, Cannons J, Bick D, Blakemore L et al (2011) A mosaic activating mutation in Akt1 associated with the Proteus syndrome. N Engl J Med 365:611–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Loibl S, Minckwitz V, Schneeweiss A (2014) PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol 32:3212–3220

    Google Scholar 

  68. Longo P, Laurenti L, Gobessi S, Sica S, Leone G, Efremov D (2008) The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood 111:846–855

    Google Scholar 

  69. Lucas C, Kuehn H, Zhao F, Niemela J, Deenick E, Palendira U, Avery D, Moens L, Cannons J, Biancalana M et al (2014) Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol 15:88–97

    Article  CAS  PubMed  Google Scholar 

  70. Maira S, Galetic I, Brazil D, Kaech S, Ingley E, Thelen M, Hemmings B (2001) Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science (New York, N.Y.) 294:374–380

    Google Scholar 

  71. Manning B, Cantley L (2007) Akt/PKB signaling: navigating downstream. Cell 129:1261–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Marshall G, Howard Z, Dry J, Fenton S, Heathcote D, Gray N, Keen H, Logie A, Holt S, Smith P et al (2011) Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. Biochem Soc Trans 39:456–459

    Article  CAS  PubMed  Google Scholar 

  73. Mayo L, Donner D (2001) A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 98:11598–11603

    Google Scholar 

  74. Medema R, Kops G, Bos J, Burgering B (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404:782–787

    Google Scholar 

  75. Menon S, Dibble C, Talbott G, Hoxhaj G, Valvezan A, Takahashi H, Cantley L, Manning B (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mills J, Hippo Y, Robert F, Chen S, Malina A, Lin CJ, Trojahn U, Wendel H, Charest A, Bronson R, Kogan S, Nadon R, Housman D, Lowe S, Pelletier J (2008) mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci USA 105:10853–10858

    Google Scholar 

  77. Munster PN, Aggarwal R, Hong D, Schellens J (2015) First-in-human phase I study of GSK2126458, an oral pan-class I phosphatidylinositol-3-kinase inhibitor, in patients with advanced solid tumor malignancies. Clin Cancer Res [Epub ahead of print]

    Google Scholar 

  78. Muranen T, Selfors L, Worster D, Iwanicki M, Song L, Morales F, Gao S, Mills G, Brugge J (2012) Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21:227–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nakae J, Park B, Accili D (1999) Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem 274:15982–15985

    Google Scholar 

  80. Nayak G, Cooper G (2012) p53 is a major component of the transcriptional and apoptotic program regulated by PI 3-kinase/Akt/GSK3 signaling. Cell Death Dis 3:e400

    Google Scholar 

  81. Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, Riddle S, Benes C, Eck M, Roberts T et al (2012) Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. Cancer Discov 2:425–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nuciforo P, Aura C, Holmes E, Prudkin L, Jimenez J, Martinez P, Ameels H, de la Peña L, Ellis C, Eidtmann H, Piccart-Gebhart M, Scaltriti M, Baselga J (2015) Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status. Ann Oncol 26:1494–1500

    Google Scholar 

  83. O’Reilly K, Rojo F, She Q-B, Solit D, Mills G, Smith D, Lane H, Hofmann F, Hicklin D, Ludwig D et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508

    Article  PubMed  PubMed Central  Google Scholar 

  84. Okkenhaug K (2013) Two Birds with one stone: dual p110δ and p110γ inhibition. Chem Biol 20:1309–1310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek S, Salpekar A, Waterfield M et al (2002) Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297:1031–1034

    CAS  PubMed  Google Scholar 

  86. Orloff M, He X, Peterson C, Chen F, Chen J-L, Mester J, Eng C (2013) Germline PIK3CA and Akt1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet 92:76–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Porstmann T, Santos C, Griffiths B, Cully M, Wu M, Leevers S, Griffiths J, Chung Y-L, Schulze A (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8:224–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rivière J-B, Mirzaa G, O’Roak B, Beddaoui M, Alcantara D, Conway R, St-Onge J, Schwartzentruber J, Gripp K, Nikkel S et al (2012) De novo germline and postzygotic mutations in Akt3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 44:934–940

    Article  PubMed  PubMed Central  Google Scholar 

  89. Robey RB, Hay N (2009) Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 19:25–31

    Google Scholar 

  90. Rodon J, Dienstmann R, Serra V, Tabernero J (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10:143–153

    Article  CAS  PubMed  Google Scholar 

  91. Rodrik-Outmezguine V, Chandarlapaty S, Pagano N, Poulikakos P, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N (2011) mTOR kinase inhibition causes feedback-dependent biphasic regulation of Akt signaling. Cancer Discov 1:248–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Saal L, Gruvberger-Saal S, Persson C, Lövgren K, Jumppanen M, Staaf J, Jönsson G, Pires M, Maurer M, Holm K et al (2008) Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet 40:102–107

    Article  CAS  PubMed  Google Scholar 

  93. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell S, Riggins G et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science (New York, N.Y.) 304:554

    Article  CAS  Google Scholar 

  94. Sancak Y, Thoreen C, Peterson T, Lindquist R, Kang S, Spooner E, Carr S, Sabatini D (2007) PRAS40 Is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25:903–915

    Article  CAS  PubMed  Google Scholar 

  95. Sancak Y, Peterson T, Shaul Y, Lindquist R, Thoreen C, Bar-Peled L, Sabatini D (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science (New York, N.Y.) 320:1496–1501

    Article  CAS  Google Scholar 

  96. Sano H, Kane S, Sano E, Mîinea C, Asara J, Lane W, Garner C, Lienhard G (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278:14599–14602

    Article  CAS  PubMed  Google Scholar 

  97. Schmit F, Utermark T, Zhang S, Wang Q, Von T, Roberts T, Zhao J (2014) PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci USA 111:6395–6400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Schwartz S, Wongvipat J, Trigwell C, Hancox U, Carver B, Rodrik-Outmezguine V, Will M, Yellen P, de Stanchina E, Baselga J, Scher H, Barry S, Sawyers C, Chandarlapaty S, Rosen N (2015) Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell 27:109–122

    Google Scholar 

  99. Serra V, Scaltriti M, Prudkin L, Eichhorn P, Ibrahim Y, Chandarlapaty S, Markman B, Rodriguez O, Guzman M, Rodriguez S, Gili M, Russillo M, Parra J, Singh S, Arribas J, Rosen N, Baselga J (2011) PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30:2547–2557

    Google Scholar 

  100. Shi Y, Yan H, Frost P, Gera J, Lichtenstein A (2005) Mammalian target of rapamycin inhibitors activate the Akt kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 4:1533–1540

    Article  CAS  PubMed  Google Scholar 

  101. Stemke-Hale K, Gonzalez-Angulo A, Lluch A, Neve R, Kuo W-L, Davies M, Carey M, Hu Z, Guan Y, Sahin A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and Akt mutations in breast cancer. Cancer Res 68:6084–6091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Stratikopoulos E, Dendy M, Szabolcs M, Khaykin A, Lefebvre C, Zhou M, Parsons R (2015) Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy. Cancer Cell 27:837–851

    Google Scholar 

  103. Tan M-H, Mester J, Ngeow J, Rybicki L, Orloff M, Eng C (2012) Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res Official J Am Assoc Cancer Res 18:400–407

    Article  CAS  Google Scholar 

  104. Taniguchi C, Kondo T, Sajan M, Luo J, Bronson R, Asano T, Farese R, Cantley L, Kahn CR (2006) Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab 3:343–353

    Google Scholar 

  105. Thorpe L, Yuzugullu H, Zhao J (2015) PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15:7–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tinkum K, White L, Marpegan L, Herzog E, Piwnica-Worms D, Piwnica-Worms H (2013) Forkhead box O1 (FOXO1) protein, but not p53, contributes to robust induction of p21 expression in fasted mice. J Biol Chem 288:27999–28008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tinsley S, Meja K, Shepherd C, Khwaja A (2014) Synergistic induction of cell death in haematological malignancies by combined phosphoinositide‐3‐kinase and BET bromodomain inhibition. Br J Haematol 170:275–278

    Google Scholar 

  108. Torbett N, Luna-Moran A, Knight Z, Houk A, Moasser M, Weiss W, Shokat K, Stokoe D (2008) A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J 415:97–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tremblay F, Brûlé S, Um S, Li Y, Masuda K, Roden M, Sun X, Krebs M, Polakiewicz R, Thomas G et al (2007) Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci 104:14056–14061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T (2014) CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26:136–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wan X, Harkavy B, Shen N, Grohar P, Helman L (2006) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26:1932–1940

    Google Scholar 

  112. Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ (2015) PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene [Epub ahead of print]

    Google Scholar 

  113. Wang R, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, White M, Reichelt J, Levine B (2012) Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science (New York, N.Y.) 338:956–959

    Article  CAS  Google Scholar 

  114. Wee S, Wiederschain D, Maira S-M, Loo A, Miller C, deBeaumont R, Stegmeier F, Yao Y-M, Lengauer C (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA 105:13057–13062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Whitman M, Kaplan D, Schaffhausen B, Cantley L, Roberts T (1985) Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315:239–242

    Google Scholar 

  116. Whitman M, Downes C, Keeler M, Keller T, Cantley L (1988) Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332:644–646

    Google Scholar 

  117. Woscholski R, Finan P, Radley E, Totty N, Sterling A, Hsuan J, Waterfield M, Parker P (1997) Synaptojanin Is the major constitutively active phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase in rodent brain. J Biol Chem 272:9625–9628

    Article  CAS  PubMed  Google Scholar 

  118. Yang W, Ching K, Tsoukas C, Berg L (2001) Tec kinase signaling in T cells is regulated by phosphatidylinositol 3-kinase and the Tec pleckstrin homology domain. J Immunol 166 387–395

    Google Scholar 

  119. Yang K, Guo Y, Stacey WC (2006) Glycogen synthase kinase 3 has a limited role in cell cycle regulation of cyclin D1 levels. BMC Cell Biol 7:33

    Google Scholar 

  120. Yang Q, Modi P, Newcomb T, Quéva C, Gandhi V (2015) Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res Official J Am Assoc Cancer Res 21:1537–1542

    Article  CAS  Google Scholar 

  121. Zhang X, Tang N, Hadden T, Rishi A (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta (BBA)—Mol Cell Res 1813:1978–1986

    Article  CAS  Google Scholar 

  122. Zhang Y, Nicholatos J, Dreier J, Ricoult S, Widenmaier S, Hotamisligil G, Kwiatkowski D, Manning B (2014) Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513:440–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhao L, Vogt P (2008) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105:2652–2657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhou B, Liao Y, Xia W, Spohn B, Lee M, Hung M (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature Cell Biol 3 245–252

    Google Scholar 

Download references

Acknowledgments

This contribution was supported by NIH grants P50-GM107618 and T32-CA009172, as well as by the Dana-Farber Leadership Council.

Author information

Authors and Affiliations

  1. Laboratory for Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA

    Sameer S. Chopra

  2. Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA

    Lewis C. Cantley

Authors
  1. Sameer S. Chopra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lewis C. Cantley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lewis C. Cantley .

Editor information

Editors and Affiliations

  1. Oncology, Head of Cancer Biology, Avera Cancer Instit Center for Precision, SIOUX FALLS, South Dakota, USA

    Nandini Dey

  2. Oncology, Head of Translational Oncology, Avera Cancer Institute Center for Preci, Sioux Falls, South Dakota, USA

    Pradip De

  3. Precision Oncology,, Avera Cancer Institute Center for, Sioux Falls, South Dakota, USA

    Brian Leyland-Jones

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this chapter

Cite this chapter

Chopra, S.S., Cantley, L.C. (2016). PI3K-Akt-mTOR Signaling in Cancer and Cancer Therapeutics. In: Dey, N., De, P., Leyland-Jones, B. (eds) PI3K-mTOR in Cancer and Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-34211-5_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-34211-5_1

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-34209-2

  • Online ISBN: 978-3-319-34211-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation