The PI3K Pathway in Cancer

The PI3k pathway and its role in cancer

Aberrant activation of the phophatidylinositol 3-kinase (PI3K) pathway is commonly observed in many human cancers, including breast and lung cancers.1-3 Activation of this pathway is mainly a result of molecular alterations in one of the pathway's key components (PI3K, Akt, or mammalian target of rapamycin [mTOR]).3 Increased activity of this pathway is often associated with tumor progression and resistance to cancer therapies.1,3,4

The oncogenic potential of the PI3K pathway is explained by 2 key observations

  • Alterations in key components of this pathway (PI3K, Akt, or mTOR) can induce cell-line transformation and tumor formation in transgenic mice3
  • Multiple molecular alterations in these key components are frequently observed in numerous human tumors3,5,6
The PI3K family

The PI3K family consists of 3 classes of PI3Ks, each with its own substrate specificity, tissue distribution, and mechanism of action. Class IA PI3Ks are the most widely implicated in cancer.7 The 4 isoforms of Class IA PI3Ks have distinct biological functions.8

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

Somatic mutations in PI3K-alpha were identified in a variety of cancer types.9 These mutations increase kinase activity and contribute to transformation. 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.8

PI3K inhibition can block growth of tumors activated by oncogenic RTKs, PI3K mutants, and/or PTEN loss of function. Inhibition strategies include ATP-competitive pan-PI3K selective inhibitors, isoform-specific PI3K inhibitors, and inhibitors targeting isoform-specific PI3K mutations.3,8

Akt functions as a component of the PI3K signaling pathway

Akt functions as a component of the PI3K signaling pathway. In cancer, Akt activity is frequently elevated owing to multiple possible alterations, including mutations of the AKT1, AKT2, and AKT3 genes; loss of function of the PTEN tumor-suppressor gene; and mutations of the PIK3CA gene.3 Akt acts as a survival kinase in many cancers.10

mTOR exists in 2 distinct intracellular complexes, mTORC1 and mTORC2

mTOR plays an important role in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy levels, oxygen levels, and mitogenic signals.11

mTOR exists in 2 distinct intracellular complexes, mTORC1 and mTORC2. Inhibition of mTORC1 unexpectedly resulted in upregulation of Akt.12

References

  1. Myers AP, Cantley LC. Targeting a common collaborator in cancer development. Sci Transl Med. 2010;2:48ps45. PMID: 20826838
  2. Song L, Xiong H, Li J, et al. Sphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-ΚB pathway in human non-small cell lung cancer. Clin Cancer Res. 2011;17:1839-1849. PMID: 21325072
  3. 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
  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. Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486:405-409. PMID: 22722202
  6. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28:1075-1083. PMID: 20085938
  7. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550-562. PMID: 19629070
  8. 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
  9. Samuels Y, Waldman T. Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol. 2010;347:21-41. PMID: 20535651
  10. Chautard E, Ouédraogo ZG, Biau J, Verrelle P. Role of Akt in human malignant glioma: from oncogenesis to tumor aggressiveness. J Neurooncol. 2014;117:205-215. PMID: 24477623
  11. 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
  12. Altomare DA, Khaled AR. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem. 2012;19:3748-3762. PMID: 22680924