Research Article

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

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Science  08 Nov 2019:
Vol. 366, Issue 6466, pp. 714-723
DOI: 10.1126/science.aaw9032

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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.

Seeing double can be a good thing

Many human breast cancers harbor activating mutations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide 3-kinase (PI3K). Clinical trials are underway to evaluate the efficacy of PI3K inhibitors in cancer patients. Vasan et al. found unexpectedly that a subset of breast cancers harbor not one—but two—PIK3CA mutations, and the mutations occur on the same allele (see the Perspective by Toker). In model systems, the double mutations hyperactivate PI3K signaling and enhance tumor growth. Preliminary analysis of clinical trial data suggests that breast cancers with double mutations are more responsive to PI3K inhibitors than those with a single mutation. PIK3CA mutational status could help identify the breast cancer patients most likely to benefit from these drugs.

Science, this issue p. 714; see also p. 685

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