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Updated: Jun 25, 2026
08:12
Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
Published on: October 5, 2020
Adaptive Feedback Signaling Through the FAK/SRC Pathway Promotes KRAS G12C Inhibitor Resistance
Hibiki Udagawa1, Yuji Shibata2, Monique B Nilsson2
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Summary
Targeting the focal adhesion kinase (FAK)/SRC pathway can overcome resistance to KRAS inhibitors like sotorasib. Combining FAK/SRC inhibitors with KRAS inhibitors enhances anti-tumor activity and improves clinical outcomes in cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS inhibitors (e.g., sotorasib, adagrasib) show clinical activity but resistance limits efficacy.
- Adaptive signaling pathways promote resistance to KRAS inhibitors.
- Novel combinatorial strategies are needed to enhance treatment outcomes.
Purpose of the Study:
- Identify pathways mediating resistance to KRAS inhibitors.
- Evaluate the synergistic potential of targeting the FAK/SRC pathway with KRAS inhibitors.
- Assess the therapeutic efficacy of combined FAK/SRC and KRAS inhibition in preclinical models.
Main Methods:
- High-throughput drug screening to identify resistance mediators.
- Preclinical studies using cell lines and xenograft models.
- Pharmacologic inhibition of FAK/SRC and KRAS pathways.
Main Results:
- FAK/SRC pathway activation mediates feedback signaling in response to KRAS inhibition.
- FAK and SRC inhibitors synergize with KRAS inhibitors in preclinical models.
- FAK/SRC inhibition resensitized resistant cells and enhanced anti-tumor activity in xenografts.
Conclusions:
- The FAK/SRC pathway is a critical mediator of adaptive resistance to KRAS inhibitors.
- Combining FAK/SRC inhibitors with KRAS inhibitors can overcome resistance and enhance anti-tumor efficacy.
- Targeting FAK/SRC represents a promising strategy to improve clinical outcomes for KRAS-mutated cancers.
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