Accumulated sotorasib-bound KRASG12C reactivates the MAPK pathway and drives sotorasib resistance via the DHX9-RAC1-PAK1 axis

  • Cell Rep. 2026 May 26;45(5):117338. doi: 10.1016/j.celrep.2026.117338.
Gongmin Zhu  1 ,  Lijiao Pei  2 ,  Jue Li  3 ,  Chenliang Zhang  1 ,  Di Ye  1 ,  Jielang Li  4 ,  Qiulin Tang  1 ,  Huixi Huang  1 ,  Huanji Xu  5 ,  Feng Bi  6
Affiliations
  • 1. Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
  • 2. Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
  • 3. Laboratory of Precision Therapeutics, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4. Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China; Clinical Trial Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5. Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China. Electronic address: [email protected].
  • 6. Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China. Electronic address: [email protected].
PMID: 42090290 DOI: 10.1016/j.celrep.2026.117338
Abstract

Sotorasib has introduced new therapeutic opportunities for Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C-mutant tumors, but resistance emerging within months poses a major clinical challenge. Mitogen-activated protein kinase (MAPK) pathway reactivation is a key driver of sotorasib resistance, yet its mechanisms remain incompletely elucidated. We observe that MAPK pathway reactivation following sotorasib treatment is largely independent of Ras activity and instead driven by accumulation of sotorasib-bound KRASG12C (soto-KRASG12C). Mechanistically, accumulated soto-KRASG12C promotes activation of the Rac family small GTPase 1 (RAC1)- p21-Activated Kinase 1 (PAK1) axis through interaction with DExD/H-box helicase 9 (DHX9), thereby reactivating the MAPK pathway. DHX9 shuttles between the nucleus and cytoplasm, and its interaction with soto-KRASG12C results in its cytoplasmic retention. Co-treatment with an Son of Sevenless 1 (SOS1) inhibitor also leads to sustained suppression of soto-KRASG12C levels. Furthermore, combining sotorasib with either a DHX9 inhibitor or an SOS1 inhibitor significantly enhances its anti-tumor efficacy in both KRASG12C-mutant and sotorasib-resistant models. These findings provide previously uncharacterized mechanistic insights to guide therapeutic strategies aimed at overcoming sotorasib resistance.

Keywords
CP: microbiology; DExD/H-box helicase 9; KRAS(G12C)-mutant tumors; MAPK pathway; drug resistance; sotorasib.
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