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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3K? inhibitors.


ABSTRACT: Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3K?) 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 p110? binding to the inhibitory subunit p85?, which relieves its catalytic inhibition, and increased p110? membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3K? inhibitors compared with single-hotspot mutations.

SUBMITTER: Vasan N 

PROVIDER: S-EPMC7173400 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Activating mutations in <i>PIK3CA</i> 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 <i>PIK3CA</i>-mutant cancer genomes and observed the presence of multiple <i>PIK3CA</i> mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double <i>PIK3CA</i> mutations are in cis on the same allele and result  ...[more]

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