PI3Kα-selective inhibitors have received FDA approval for use in breast cancer, but clinical-acquired resistance to these inhibitors is not well understood. Using serial liquid biopsies and molecular profiling of rapid autopsies from 39 patients with advanced breast cancer that developed acquired resistance to orthosteric PI3Kα inhibitors, Varkaris, Fece de la Cruz, Martin, and colleagues showed that 50% of patients acquire genomic alterations in the PI3K pathway and identified secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Use of the allosteric, pan-mutant-selective PI3Kα inhibitor RLY-2608 was able to overcome resistance induced by all mutations, providing insight into potential strategies to improve outcomes.

See article, p. 227.

PIK3CA is mutated in approximately 40% of hormone receptor-positive (HR+) breast cancer. Standard-of-care treatment with the orthosteric inhibitor alpelisib leads to dose-limiting hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Varkaris and colleagues discovered a cryptic allosteric pocket that...

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