Editorial: PI3 Kinase Pathway Mutations in Human Cancers

JAMA Oncology
 

Editorial 

References

Comments

 

International genome analysis studies have now cataloged mutations in thousands of human cancers. An assessment of these studies using cBioPortal^1,2 and by Tamborero et al³ shows that the phosphatidylinositol 3-kinase (PI3K) pathway genes, including PIK3CA, PTEN, and AKT1, are among the most commonly mutated in human cancers of all types. Only TP53 is mutated more frequently. PI3K signaling typically is activated by signaling from tyrosine kinases and other receptors and proceeds through recruitment of a regulatory subunit (eg, p85α encoded by PIK3R1) and a catalytic subunit (eg, p110α, encoded by PIK3CA) to produce phosphatidylinositol-3,4,5-trisphosphate (PIP₃). PIP₃ recruits protein kinase B (AKT) that, in turn, stimulates growth and cell survival. This process is negatively regulated by PIP₃ dephosphorylation by the tumor suppressor, PTEN. PI3K pathway mutations enhance signaling along the pathway directly in the case of PIK3CA and AKT1 or by inactivating the negative regulator, PTEN.⁴

This is information has fueled the development of a growing number of therapeutic agents that target the PI3K pathway.⁵ Notable examples include idelalisib, buparlisib, duvelisib, and alpelisib (ClinicalTrials.gov). These are being considered for assessment in a broad range of cancers carrying PI3K-activating aberrations. Importantly, the frequency of activating events varies considerably among cancer types. An analysis of 87 published studies of diverse cancer types reported in cBioPortal^1,2 shows that mutations in PIK3CA, PTEN, and AKT1 occur in more than 40% of cancers of the uterus, lung, breast, prostate, brain, and head and neck. However, few aberrations involving these genes have been found in pancreatic adenocarcinoma, central nervous system lymphoma, small cell carcinoma of the ovary, liver hepatocellular carcinoma, neuroblastoma, and thymic epithelial tumors. Notably, genome studies published to date were been intended as aberration discovery efforts and were not designed to assess the frequencies of aberrations in the overall clinical population. Moreover, the tumors analyzed often were selected to be relatively large and sufficiently necrosis free to enable high-quality genomic analysis. This may impose some selection bias. In addition, some studies were restricted in ethnic diversity.

 Millis et al⁶ now present a study of the frequency with which PIK3CA, PTEN, and AKT1 and other “actionable” genes are aberrant in a broad range of human cancers. They assessed aberrations involving these genes in 19 784 consecutive diverse solid tumors submitted by clinicians in more than 60 countries.... 

Reference:

Original Investigation (open access)

Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors

 ...The PI3K pathway can be constitutively activated by genomic aberrations in cancer.⁴ Common alterations include (1) activating mutations or/and amplification of the catalytic subunit alpha (PIK3CA),^5,6 (2) loss of PTEN,⁷ and (3) mutation and/or amplification of AKT, a serine/threonine-specific protein kinase.⁸ These alterations are sufficient to induce tumorigenesis in preclinical models.^9- 11 Genomic alterations of the PI3K pathway have been observed in diverse solid tumors, including, but not limited to, breast, endometrial, epithelial ovarian, prostate, bladder, colorectal, gastric, and pancreatic cancer, as well as various squamous cell cancers, melanoma, and glioblastoma.^12- 14 However, these studies generally had small sample sizes, and it is difficult to capture the true frequency of alterations owing to the different techniques used in each study. The Cancer Genome Atlas has provided the most comprehensive evaluation to date, including an analysis of 12 major cancers and several studies in individual cancers.^15- 17....