| Literature DB >> 31699932 |
Pedram Razavi1,2, Jared L Johnson3, Hong Shao1, Neil Vasan1,2,3, Hardik Shah4, Alesia Antoine4, Erik Ladewig1, Alexander Gorelick1,5, Ting-Yu Lin3, Eneda Toska1, Guotai Xu1, Abiha Kazmi1, Matthew T Chang6, Barry S Taylor1,5,7, Maura N Dickler2,8, Komal Jhaveri2, Sarat Chandarlapaty1,2, Raul Rabadan9, Ed Reznik5,7, Melissa L Smith4,10, Robert Sebra4,10,11, Frauke Schimmoller6, Timothy R Wilson6, Lori S Friedman12, Lewis C Cantley3, Maurizio Scaltriti13,14, José Baselga13,2.
Abstract
Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) 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 p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.Entities:
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Year: 2019 PMID： 31699932 PMCID： PMC7173400 DOI： 10.1126/science.aaw9032
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728