Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Ka inhibitors.

Authors: Vasan, Neil and Razavi, Pedram and Johnson, Jared L and Shao, Hong and Shah, Hardik and Antoine, Alesia and Ladewig, Erik and Gorelick, Alexander and Lin, Ting-Yu and Toska, Eneda and Xu, Guotai and Kazmi, Abiha and Chang, Matthew T and Taylor, Barry S and Dickler, Maura N and Jhaveri, Komal and Chandarlapaty, Sarat and Rabadan, Raul and Reznik, Ed and Smith, Melissa L and Sebra, Robert and Schimmoller, Frauke and Wilson, Timothy R and Friedman, Lori S and Cantley, Lewis C and Scaltriti, Maurizio and Baselga, José

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, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Journal: Science
DOI: 10.1126/science.aaw9032
Year: 2019

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