PI3K-Driven Wild-Type RAS Activation Fuels KRAS Inhibitor Resistance
Publication Title: PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.
Summary
- Question
- This study examined how the phosphoinositide 3-kinase (PI3K) signaling pathway regulates resistance to KRAS inhibitors in pancreatic ductal adenocarcinoma (PDAC). The researchers aimed to understand the mechanisms through which PI3K drives wild-type RAS activity, leading to therapeutic resistance.
- Why it Matters
- KRAS mutations are present in over 90% of PDAC cases, making KRAS a key therapeutic target. However, resistance to KRAS inhibitors remains a major challenge. Understanding how PI3K sustains wild-type RAS signaling despite KRAS inhibition is crucial for improving therapeutic strategies. This research highlights the potential for combined PI3K and KRAS targeting to overcome resistance, offering hope for more effective treatments for PDAC and other KRAS-driven cancers.
- Methods
- The researchers used a combination of molecular biology techniques, including CRISPR gene editing, live-cell imaging, protein proximity labeling, and drug treatments. They studied PDAC cells with and without KRAS mutations and employed various inhibitors to assess the role of PI3K in wild-type RAS signaling and its interaction with other cellular pathways.
- Key Findings
- The study found that PI3K plays a central role in resistance to KRAS inhibitors by activating wild-type RAS signaling. PI3K facilitates the recruitment of the scaffold protein GAB1 to the plasma membrane, forming complexes with proteins like EGFR, SHP2, and SOS1, which drive RAS and MAPK signaling. Inhibiting PI3K reduced wild-type RAS activity and enhanced sensitivity to KRAS inhibitors. Conversely, PI3K activation diminished the effectiveness of KRAS inhibitors.
- Implications
- These findings redefine the understanding of RAS signaling, showing that PI3K can act upstream to regulate wild-type RAS activity, challenging the conventional view of PI3K as solely a downstream effector. Clinically, targeting PI3K alongside KRAS could improve outcomes for patients with KRAS-mutant PDAC. Additionally, the study suggests that PI3K-driven resistance mechanisms may apply to other cancers, broadening the potential impact of this research.
- Next Steps
- The authors propose further research to explore the structural details of PI3K-dependent signaling complexes and validate these findings in animal models and diverse cancer types. They also suggest investigating the therapeutic potential of combining PI3K and KRAS inhibitors in clinical trials.
- Funding Information
- This research was supported by the National Institutes of Health (NIH), including the NIH Director’s New Innovator Award (DP2-CA248136), the NCI Mentored Clinical Scientist Research Career Development Award (K08-CA2080016), NCI R01-CA276108, and the Yale Comprehensive Cancer Center Support Grant (P30-CA016359). Additional NIH support included funding from the National Institute of General Medical Sciences (NIGMS) (R35-GM147095, R01-GM137031, and RM1-GM149406) and the NCI Research Supplement (R01-CA276108-03S1). This work also received support from the American Cancer Society Institutional Research Grant (IRG 17-172-57) and the Lustgarten Foundation Therapeutics-Focused Research Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Full Citation
Ge X, Singh J, Li W, Markham CS, Ruiz CF, Stites EC, Bhattacharyya M, Liu Y, Muzumdar MD. PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition. Cancer Res 2026 PMID: 42095550, DOI: 10.1158/0008-5472.CAN-25-3625.
Authors
Mandar Deepak Muzumdar, MD
Last AuthorAssociate Professor of Genetics and of Internal Medicine (Medical Oncology).