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Researchers Says That Cancer Is A Numerous Gain Of Function Mutations And Gene Amplifications

Researchers Says That Cancer Is A Numerous Gain Of Function Mutations And Gene Amplifications

Cancer is predominantly a genetic disease. Numerous gain-of-function mutations and gene amplifications that promote cell growth and survival have been identified in human cancer genomes through the efforts of large-scale sequencing projects. One of the most frequently mutated oncogenes in all human cancers is PIK3CA [phosphatidylinositol 4,5-bisphosphate (PIP2) 3-kinase catalytic subunit α], which encodes the catalytic subunit (p110α) of phosphoinositide 3-kinase (PI3K) Oncogenic mutations in PIK3CA hyperactivate downstream signaling and promote phenotypes associated with malignancy. On page 714 of this issue, Vasan et al. find that double mutations (two different mutations in one allele) in PIK3CA occur with much higher frequency in cancer genomes, particularly breast cancers, than previously thought. Double mutations result in increased PI3K pathway activity and tumor growth and predict increased sensitivity of human breast cancer to PI3K inhibitors.

Small-molecule inhibitors that target the PI3K pathway for cancer therapy have been developed. In May 2019, the U.S. Food and Drug Administration approved alpelisib, a p110α inhibitor for the treatment of postmenopausal women with estrogen receptor–positive (ER+), PIK3CA-mutant advanced or metastatic breast cancer, in combination with the ER antagonist fulvestrant. Approval was prompted by a phase 3 clinical trial that showed a doubling of progression-free survival in patients with ER+ and PIK3CA-mutant breast cancer treated with alpelisib and fulvestrant, compared with patients with wild-type PIK3CA . A recent study also identified an exceptional responder (a patient who responded to monotherapy in early clinical trials). This patient had double PIK3CA mutations, whereas the majority of recurrent PIK3CA mutations identified in sequencing projects were mostly heterozygous, single mutations.