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(Phospho)proteomic Profiling Reveals Mutation-Specific Adaptive Signaling to PI3Kα Inhibition in PIK3CA Mutant Breast
Fujia Wang1,2, Maarten Altelaar1,2, Kelly E Stecker1,2
1Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Journal of Proteome Research
|May 28, 2026
Summary
Activating PIK3CA mutations drive breast cancer. Targeting PI3K and MAPK pathways together shows promise for improving treatment efficacy in PIK3CA-mutant breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Activating PIK3CA mutations are common drivers in breast cancer, with E545K and H1047R being prevalent.
- Current PI3K inhibitors have limited efficacy in some cases, necessitating a deeper understanding of mutation-specific signaling.
Purpose of the Study:
- To compare E545K and H1047R mutant breast epithelial cells to identify mutation-specific signaling programs and growth phenotypes.
- To investigate responses to PI3Kα inhibition, with or without insulin, and delineate adaptive signaling mechanisms.
Main Methods:
- Utilized integrated growth assays and quantitative proteomic and phosphoproteomic profiling.
- Compared E545K and H1047R mutant breast epithelial cells under various conditions.
Main Results:
- Uncovered mutation-specific signaling architectures and differential sensitivities to PI3Kα inhibition.
- Identified basal MAPK activation with divergent phosphorylation dynamics in distinct PIK3CA mutants.
- Observed insulin-induced bypass signaling counteracting PI3Kα inhibition and MEK inhibition alone suppressing growth.
Conclusions:
- Findings reveal mutation-specific adaptive signaling in PIK3CA-driven breast cancer.
- Support combined PI3Kα and MAPK pathway inhibition as a therapeutic strategy for improved efficacy.
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