Explore PI3K-Akt-mTOR

Understanding the PI3K-Akt-mTOR pathway

The PI3K-Akt-mTOR signaling pathway is a key regulator of normal cellular processes involved in cell growth, proliferation, motility, survival, and apoptosis. Aberrant activation of the PI3K-Akt-mTOR pathway results in the survival and proliferation of tumor cells in many human cancers.1

The PI3K-Akt-mTOR signaling pathway

Phosphatidylinositol 3-kinase (PI3K), Akt (a serine/threonine kinase also known as PKB), and mammalian target of rapamycin (mTOR) are 3 major junctions in the pathway, and are typically activated by upstream signaling of tyrosine kinases and other receptor molecules such as hormones and other mitogenic factors.2

Class IA PI3Ks are a subgroup of the PI3K family. They are activated by receptor tyrosine kinases (RTKs) and their primary role is to convert phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Akt is activated following recruitment to the cell surface by PIP3, and acts downstream of PI3K to regulate many cellular processes, including cell survival, proliferation, and growth.3 mTOR is a key protein in the pathway that acts both upstream and downstream of Akt.4 mTOR is active in 2 different multiprotein complexes, target of rapamycin complex (TORC) 1 and 2, and regulates the protein synthesis necessary for cell growth, proliferation, angiogenesis, and other cellular endpoints.4,5

The PI3K-Akt-mTOR signaling pathway regulates cell survival and proliferation.6

Image: The PI3K-Akt-mTOR signaling pathway

PTEN=phosphatase and tensin homolog deleted on chromosome; FOX0=forkhead box 0.

The PI3K-Akt-mTOR pathway and its role in cancer

Aberrant activation of the PI3K-Akt-mTOR pathway is commonly observed in many human cancers, including breast, lung, and prostate.3,7,8 Activation of this pathway is mainly a result of molecular alterations in one of the pathway's 3 key components: PI3K, Akt, or mTOR.7 Increased activity of this pathway is often associated with tumor progression and resistance to cancer therapies.7,8

Image: PI3K

The PI3K family consists of 3 classes of PI3Ks, each with its own substrate specificity, tissue distribution, and mechanism of action.9-11 Class IA PI3Ks are the most widely implicated of the 3 classes in cancer.12 The 4 isoforms of Class IA PI3Ks have distinct biological functions.10

  • PI3K-alpha
  • PI3K-beta
  • PI3K-gamma
  • PI3K-delta

Somatic mutations in PI3K-alpha have been identified in a variety of cancer types.11 These mutations increase kinase activity and contribute to transformation.12 Mutations in PIK3CA (the gene coding for PI3K-alpha) are prevalent in a diverse variety of cancer types, making PIK3CA the most commonly mutated oncogene.10 The PI3K signaling pathway is altered in nearly all patients with advanced-stage prostate cancer, with biallelic loss of tumor suppressor PTEN being the most common somatic mutation.13

PI3K inhibition may block growth of tumors activated by oncogenic RTKs, PI3K mutants, and/or PTEN loss of function. Inhibition strategies include adenosine 5'-triphosphate (ATP)-competitive pan-PI3K selective inhibitors, isoform-specific PI3K inhibitors, and inhibitors targeting isoform-specific PI3K mutations.10,14

Alterations in any of the key components of this pathway (PI3K, Akt, and mTOR) can induce cell line transformation and tumor formation in transgenic mice.14 Preclinical knockout of PI3K blocked oncogenic transformation.12 Knockout or suppression of Akt or mTOR has inhibited tumor growth and invasiveness in animal models.13,15 Multiple molecular alterations in these key components are frequently observed in a wide range of human tumors.3,14

The role of Akt in cancer

Image: Akt

Akt, a serine/threonine protein kinase, is a downstream effector of PI3K.16 There are 3 highly homologous Akt isoforms (Akt 1, 2, and 3) that are encoded by separate genes and share over 80% amino acid sequence identity in mammalian cells.17

Akt is one of the most frequently activated protein kinases in human cancers. Hyperactivation of Akt may induce cell growth and proliferation, and contribute to apoptotic resistance.16

In cancer, Akt activity is frequently elevated due to oncogenic growth factors, angiogenic factors, cytokines, steroid hormones (estrogen and androgen), and genetic alterations, including mutations and/or amplifications of the AKT1, AKT2, and AKT3 genes; loss of function of the PTEN tumor-suppressor gene; and mutations of the PIK3CA gene.15,18 Inactivation of PTEN and missense alleles of PIK3CA have been associated with constitutive activation of Akt. Akt activities have been correlated with various clinicopathologic parameters such as advanced disease and/or poor prognosis in a number of tumors.19

The oncogenic potential of the Akt pathway is further supported by the fact that a murine model-based conditional Pten deletion, leading to increased activation of Akt signaling, may result in the development of metastatic cancer.13 Ectopic expression of constitutive active Akt resulted in in vitro and in vivo oncogenic transformation.15 In addition, downregulation or knockdown of Akt by antisense or small (or short) interfering RNA (siRNA) significantly reduced tumor growth and invasiveness, and induced apoptosis and cell growth arrest only in tumor cells overexpressing Akt.15

The role of mTOR in cancer

Image: mTOR

mTOR is a conserved serine/threonine kinase that plays an important role in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy levels, oxygen levels, and mitogenic signals.12,20 mTOR exists in 2 distinct intracellular complexes, mammalian target of rapamycin complex (mTORC) 1 and 2.

mTORC1 is mainly involved in the regulation of ribosomal biogenesis and protein synthesis. Activation of mTORC1 is achieved through PI3K and Akt, while the TSC1/TSC2 complex (tumor-suppressor genes mutated in the tumor syndrome TSC [tuberous sclerosis complex]) is responsible for mTORC1 inhibition. Upon activation by growth factors, the kinase activity of mTORC2 is directed toward several downstream factors, including Akt and protein kinase C-alpha. mTORC2 also controls the activity of GTPases (hydrolase enzymes that can bind and hydrolyze guanosine triphosphate [GTP]; eg, Rac and Rho) involved in cellular migration, actin cytoskeleton regulation, and cell survival.21 Aberrant activation of the mTOR pathway has been implicated in a variety of malignancies, including breast cancer, lymphoma, and renal cell carcinoma.22

mTOR conditional knockout inhibited tumorigenesis in PTEN-deficient preclinical models.13 In addition, mTOR inhibitors demonstrated antitumor activity in endometrial cancer cell lines, with the greatest activity seen in cells with PIK3CA and/or PTEN mutations.4

The involvement of the PI3K-Akt-mTOR pathway in resistance

Preclinical data suggest that the PI3K-Akt-mTOR pathway may be upregulated as a result of targeting other signaling pathways.

  • The PI3K pathway has been implicated as a key player in the development of resistance to endocrine therapy23
  • The activation of the PI3K pathway has been implicated in de novo and acquired treatment resistance to targeted therapies in multiple tumor types23
  • Repression of the androgen receptor in prostate cancer has been shown in preclinical models to induce Akt activity, indicating the existence of a reciprocal feedback mechanism13,24
  • It has been reported that many tumors upregulate Akt in order to acquire resistance to standard chemotherapies and agents that inhibit the human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR) signaling cascades25
  • Inhibition of mTORC1 complex resulted in the upregulation of the Akt pathway, indicating the existence of a feedback loop26

Combination approaches that include targeting both the PI3K-Akt-mTOR pathway and other treatment modalities may be viable strategies to address resistance mechanisms.13,23,24

References

  1. Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64. PMID: 24782981
  2. Ruggero D, Sonenberg N. The Akt of translational control. Oncogene. 2005;24:7426-7434. PMID: 16288289
  3. Myers AP, Cantley LC. Targeting a common collaborator in cancer development. Sci Transl Med. 2010;2:48ps45. doi:10.1126/scitranslmed.3001251. Accessed December 8, 2016. PMID: 20826838
  4. Slomovitz BM, Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. 2012;18:5856-5864. PMID: 23082003
  5. Hung CM, Garcia-Haro L, Sparks CA, Guertin DA. mTOR-dependent cell survival mechanisms. Cold Spring Harb Perspect Biol. 2012;4:a008771. doi: 10.1101/cshperspect.a008771. Accessed December 5, 2016. PMID: 23124837
  6. Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol. 2014;90:197-207. PMID: 24863259
  7. Sarris EG, Saif MW, Syrigos KN. The biological role of PI3K pathway in lung cancer. Pharmaceuticals. 2012;5:1236-1264. PMID: 24281308
  8. Morgan TM, Koreckij TD, Corey E. Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets. 2009;9:237-249. PMID: 19275762
  9. Cantrell DA. Phosphoinositide 3-kinase signalling pathways. J Cell Sci. 2001;114:1439-1445. PMID: 11282020
  10. Gabelli SB, Mandelker D, Schmidt-Kittler O, Vogelstein B, Amzel LM. Somatic mutations in PI3Kα: structural basis for enzyme activation and drug design. Biochim Biophys Acta. 2010;1804:533-540. PMID: 19962457
  11. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation, and therapeutic targeting. Nat Rev Cancer. 2015;15:7-24. PMID: 25533673
  12. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627-644. PMID: 19644473
  13. Statz CM, Patterson SE, Mockus SM. mTOR inhibitors in castration-resistant prostate cancer: a systematic review. Targ Oncol. 2017;12:47-59. PMID: 27503005
  14. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10:143-153. PMID: 23400000
  15. Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene. 2005;24:7482-7492. PMID: 16288295
  16. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26:1932-1940. PMID: 17001314
  17. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005;8:179-183. PMID: 16169463
  18. Malanga D, Scrima M, De Marco C, et al. Activating E17K mutation in the gene encoding the protein kinase AKT in a subset of squamous cell carcinoma of the lung. Cell Cycle. 2008;7:665-669. PMID: 18256540
  19. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24:7455-7464. PMID: 16288292
  20. Zhou H, Huang S. Role of mTOR signaling in tumor cell motility, invasion and metastasis. Curr Protein Pept Sci. 2011;12:30-42. PMID: 21190521
  21. Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. 2012;13:1886-1918. PMID: 22408430
  22. Advani SH. Targeting mTOR pathway: a new concept in cancer therapy. Indian J Med Paediatr Oncol. 2010;31:132-136. PMID: 21584218
  23. LoRusso PM. Inhibition of PI3K/Akt/mTOR pathway in solid tumors. J Clin Oncol. 2016;34:JCO590018. doi:10.1200/JCO.2014.59.0018. Accessed November 1, 2016. PMID: 27621407
  24. Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr Relat Cancer. 2013;20:R83-R99. PMID: 23456430
  25. Huang WC, Hung MC. Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc. 2009;108:180-194. PMID: 19293033
  26. Gupta M, Hendrickson AEW, Yun SS, et al. Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. Blood. 2012;119:476-487. PMID: 22080480

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