Journal Article

Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors

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

2019

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: 1-Phosphatidylinositol 3-kinase / Alleles / Binding / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer / Carcinogenesis - genetics / Cell Line, Tumor / Cell proliferation / Class I Phosphatidylinositol 3-Kinases - chemistry / Class I Phosphatidylinositol 3-Kinases - genetics / Class I Phosphatidylinositol 3-Kinases - metabolism / Class Ia Phosphatidylinositol 3-Kinase - chemistry / Class Ia Phosphatidylinositol 3-Kinase - metabolism / Clinical trials / Coding / Disruption / Drug Resistance, Neoplasm - genetics / Female / Genomes / Humans / Inhibitors / Kinases / Lipids / Mutation / Mutation hot spots / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - pathology / Phosphoinositide-3 Kinase Inhibitors - pharmacology / Phosphoinositide-3 Kinase Inhibitors - therapeutic use / Protein Binding / Protein Domains / Sensitivity analysis / Signaling / Thiazoles - pharmacology / Tumors