Authors
Michael W Lero, Jennifer S Morgan, Michael-Anthony Card, Lihua Julie Zhu, Junhui Li, Rui Li, Quyen Thu Bui, Emma Mohlmann, Hira L Goel, Leslie M Shaw
Published in
The Journal of biological chemistry. Pages 113426. Aug 10, 2026. Epub Aug 10, 2026.
Abstract
Activating mutations in PI3K are one of the most frequent mutations in breast cancer and are associated with worse patient outcomes in many breast cancer subtypes. Despite intense interest, cancer treatments that target the PI3K pathway have been only modestly effective due to intrinsic and acquired resistance mechanisms which reactivate PI3K signaling. Here, we characterize a feedback mechanism by which PI3K pathway inhibitors increase insulin receptor substrate 2 (IRS2) abundance and demonstrate the role of IRS2 in promoting resistance to these drugs. In PIK3CA mutant breast tumors and cell lines, there is a significant reduction in IRS2 mRNA and protein abundance which is reversed by PI3K pathway inhibition and mediated by the transcription factors FOXO1 and FOXO3. PIK3CA mutations do not alter IRS1 expression. IRS2 confers resistance to PI3K pathway inhibition by sustaining PI3K signaling in PIK3CA mutant, but not wild-type breast cancer cells. Increased IRS2 abundance also correlates with PI3K pathway inhibitor resistance across PIK3CA mutant cancer cell lines from a variety of tissues. The clinical relevance of these findings is highlighted by the frequency of PI3K mutations in cancer and the identification of a new target to address the challenges associated with prior efforts to block the reactivation of PI3K signaling during PI3K inhibition.
PMID:
42575435
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.
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