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Research Watch

PIK3CA Double Mutations in Cis May Predict PI3Kα-Inhibitor Response

DOI: 10.1158/2159-8290.CD-RW2019-172 Published January 2020
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  • Major Finding: Cis double PIK3CA mutations are common in cancers and increase sensitivity to PI3Kα inhibitors.

  • Mechanism: Kinase activity was increased due to disrupted p110α–p85α binding and increased membrane binding.

  • Impact: The presence of cis PIK3CA mutations may be a biomarker for PI3Kα-inhibitor response.

PIK3CA, encoding p110α, the catalytic subunit of PI3Kα, is one of the most commonly mutated genes in cancer. Some PI3Kα inhibitors are in the pipeline or have been approved for cancer treatment, but research on which patients are likely to respond is needed. Vasan and colleagues analyzed data from a prior phase I clinical trial and noticed that patients with ER+ metastatic breast cancer treated with the combination of an aromatase inhibitor and the PI3Kα inhibitor alpelisib may have been more likely to respond if they had double mutations in PIK3CA. This prompted a more in-depth search for the effects of PIK3CA double mutations, which revealed that such mutations are common in breast and other cancers, and most often existed in cis (on the same allele). In vitro and in vivo experiments demonstrated that double PIK3CA mutations in cis caused greater activation of the PI3K pathway and greater increases in proliferation than single mutations. Biochemical experiments indicated that the cis double mutations caused increased membrane binding by p110α and may have disrupted binding between p110α and the inhibitory PI3Kα subunit p85α, both of which could have contributed to an observed increase in basal kinase activity. In vitro, cis double mutations in PIK3CA led to increased sensitivity to PI3K inhibition compared with single mutations, possibly because hyperactivation of PI3K signaling caused by the combination of mutations promoting membrane binding and disrupting p110α–p85α interactions increased dependence on the PI3K pathway. Confirming the initial findings that suggested the clinical relevance of double mutations in PIK3CA, analysis of data from the SANDPIPER phase III clinical trial of the PI3Kα/δ/γ inhibitor taselisib with fulvestrant in patients with ER+ metastatic breast cancer revealed that the overall response rate was better in patients with multiple mutations in PIK3CA rather than one. These findings provide mechanistic insight into oncogenesis in PIK3CA-mutant cancers and indicate that the presence of cis PIK3CA double mutations may be a useful biomarker for PI3Kα-inhibitor response.

Vasan N, Razavi P, Johnson JL, Shao H, Shah H, Antoine A, et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science 2019;366:714–23.

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 10 (1)
January 2020
Volume 10, Issue 1
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PIK3CA Double Mutations in Cis May Predict PI3Kα-Inhibitor Response
Cancer Discov January 1 2020 (10) (1) OF6; DOI: 10.1158/2159-8290.CD-RW2019-172

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PIK3CA Double Mutations in Cis May Predict PI3Kα-Inhibitor Response
Cancer Discov January 1 2020 (10) (1) OF6; DOI: 10.1158/2159-8290.CD-RW2019-172
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