Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Ka inhibitors Journal Article
| Authors: | Vasan, N.; Razavi, P.; Johnson, J. L.; Shao, H.; Shah, H.; Antoine, A.; Ladewig, E.; Gorelick, A.; Lin, T. Y.; Toska, E.; Xu, G.; Kazmi, A.; Chang, M. T.; Taylor, B. S.; Dickler, M. N.; Jhaveri, K.; Chandarlapaty, S.; Rabadan, R.; Reznik, E.; Smith, M. L.; Sebra, R.; Schimmoller, F.; Wilson, T. R.; Friedman, L. S.; Cantley, L. C.; Scaltriti, M.; Baselga, J. |
| Article Title: | Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Ka inhibitors |
| Abstract: | Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Ka) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110a binding to the inhibitory subunit p85a, which relieves its catalytic inhibition, and increased p110a membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Ka inhibitors compared with single-hotspot mutations. Copyright © 2019 The Authors. |
| Keywords: | signal transduction; controlled study; human tissue; unclassified drug; gene mutation; major clinical study; mutation; nonhuman; cell proliferation; mouse; allele; gene; metastasis; protein protein interaction; lipid; animal experiment; animal model; aromatase inhibitor; cohort analysis; gene frequency; in vivo study; in vitro study; enzyme activity; inhibitor; phosphatidylinositol 3 kinase; clonal variation; drug response; carcinogenicity; mutation rate; catalysis; tumor growth; codon; tumor; drug sensitivity; pik3ca gene; catalyst; predictive value; mutant; phosphatidylinositol 3 kinase inhibitor; protein lipid interaction; inhibition; membrane; peptides and proteins; brucellosis; estrogen receptor positive breast cancer; cancer; human; priority journal; article; alpelisib; nih 3t3 cell line; gdc 0077; protein p110alpha; protein p85alpha; mcf-10a cell line |
| Journal Title: | Science |
| Volume: | 366 |
| Issue: | 6466 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2019-11-08 |
| Start Page: | 714 |
| End Page: | 723 |
| Language: | English |
| DOI: | 10.1126/science.aaw9032 |
| PUBMED: | 31699932 |
| PROVIDER: | scopus |
| PMCID: | PMC7173400 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
