PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition
- Cancer Res. 2026 Aug 4;86(15):3819-3837. doi: 10.1158/0008-5472.CAN-25-3625.
- 1. Yale Cancer Biology Institute, Yale University, West Haven, Connecticut.
- 2. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
- 3. Translational Molecular Medicine, Pharmacology, and Physiology Program, Yale University, New Haven, Connecticut.
- 4. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
- 5. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
- 6. Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, Connecticut.
- 7. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut.
- 8. Yale Cancer Center and Smilow Cancer Hospital, Yale University, New Haven, Connecticut.
- 9. Department of Biomedical Informatics and Data Science, Yale University School of Medicine, New Haven, Connecticut.
- 10. Department of Internal Medicine, Section of Medical Oncology and Hematology, Yale University School of Medicine, New Haven, Connecticut.
Despite the availability of Ras inhibitors and the dependence of >90% of pancreatic ductal adenocarcinomas (PDAC) on oncogenic KRAS mutations, resistance to KRAS inhibition remains a serious obstacle. We showed here that phosphoinositide 3-kinase (PI3K) plays a major role in this resistance through upstream activation of wild-type (WT) Ras signaling-beyond its known KRAS effector function. The combination of proximity labeling, CRISPR screening, live-cell imaging, and functional assays revealed that PI3K orchestrates phosphoinositide-mediated GAB1 recruitment to the plasma membrane, nucleating assembly of Ras signaling complexes that activate mitogen-activated protein kinase (MAPK) in an EGFR/SHP2/SOS1-dependent manner. Inhibiting PI3K enhanced sensitivity to mutant-specific KRAS inhibitors in PDAC cells, including in cells with clinically identified PIK3CA mutations. These findings refine RAS-PI3K signaling paradigms, reveal that PI3K-driven WT Ras activation drives resistance to KRAS inhibition, and illuminate avenues for augmenting KRAS-targeted therapies in PDAC.
Significance: PI3K plays a functional upstream role in assembling wild-type Ras signaling complexes that confer KRAS inhibitor resistance, providing a rationale for combined targeting of PI3K and KRAS in Pancreatic Cancer.