2. Academic Validation
  3. EGFR blockade confers sensitivity to pan-RAS inhibitors in KRAS-mutated cancers

EGFR blockade confers sensitivity to pan-RAS inhibitors in KRAS-mutated cancers

  • Cell Oncol (Dordr). 2025 Jul 10. doi: 10.1007/s13402-025-01075-4.
Junling Han # 1 2,  Bo Yu # 3 2,  Jianan Jing # 4 3 2,  Xiaoyu He 3 2,  Yunfen Hua 5,  Guotai Xu 6 7
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
  • 2 National Institute of Biological Sciences, 7 Science Park Road ZGC Life Science Park, Beijing, China.
  • 3 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • 4 College of Life Sciences, Beijing Normal University, Beijing, China.
  • 5 College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China. [email protected].
  • 6 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. [email protected].
  • 7 National Institute of Biological Sciences, 7 Science Park Road ZGC Life Science Park, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 40637801 DOI: 10.1007/s13402-025-01075-4
Abstract

Introduction: KRAS is one of the most commonly occurring mutated oncogene in human cancers. Development of KRAS G12C or G12D inhibitors exhibit promising clinical activities, but patients harboring Other hotspot KRAS mutations cannot benefit from those strategies. Recent development in pan-RAS inhibitors have broad therapeutic implications and merit clinical investigation. However, intrinsic and acquired drug resistance caused by tumor heterogeneity greatly limit the clinical application, posing a significant challenge in this field.

Results: In this study, through CRISPR/Cas9 sgRNA screening using a human kinome sgRNA library, EGFR was discovered to correlate with the sensitivity of KRAS-mutated tumors to pan-RAS inhibitor RMC-7977. Through multiple in vitro cell proliferation or viability assays, EGFR loss or pharmacological EGFR inhibition significantly enhances the effectiveness of pan-RAS inhibitors in multiple KRASG12C or KRASG12D Cancer cell lines, disregarding their cellular origins. Mechanistically, co-inhibition of EGFR and pan-RAS may further dampen the RTK-RAS-RAF-MEK-ERK pathway activation than either alone, thereby enhancing the anti-tumor activity of pan-RAS inhibitors. Strikingly, with the LL/2 syngeneic mice tumor model, the combination of pan-RAS inhibitors and EGFR inhibitors demonstrated more significant in vivo therapeutic efficacy compared to either single agent.

Conclusion: In conclusion, this study employed high-throughput CRISPR/Cas9 sgRNA screening to identify the enhanced anti-cancer effects when combining EGFR inhibitors with pan-RAS inhibitors in multiple human KRAS-mutated Cancer cell lines as well as a mouse syngeneic tumor model. This synergy underscores the potential for a combinational therapy strategy, leveraging EGFR and pan-RAS inhibitors to improve treatment outcomes for patients with KRAS-driven cancers.

Keywords

KRAS-mutated cancer; CRISPR/Cas9 sgRNA screening; Combinational therapy; EGFR inhibitors; Pan-RAS inhibitors; RTK-RAS-RAF-MEK-ERK pathway.

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