2. Academic Validation
  3. YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis

YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis

  • JCI Insight. 2024 Dec 20;9(24):e178535. doi: 10.1172/jci.insight.178535.
Wang Yang 1 2 3,  Ming Zhang 2 3,  Tian-Xing Zhang 4,  Jia-Hui Liu 2 3,  Man-Wei Hao 4,  Xu Yan 5,  Haicheng Gao 4,  Qun-Ying Lei 6 7 8,  Jiuwei Cui 1,  Xin Zhou 1 2 3
Affiliations

Affiliations

  • 1 Cancer Center, and.
  • 2 Cancer Research Institute of Jilin University, The First Hospital of Jilin University, Changchun, China.
  • 3 International Center of Future Science, and.
  • 4 School of Pharmaceutical Sciences, Jilin University, Changchun, China.
  • 5 Pathological Diagnostic Center, The First Hospital of Jilin University, Changchun, China.
  • 6 Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, School of Basic Medical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Shanghai Key Laboratory of Radiation Oncology, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China.
  • 7 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 8 State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
PMID: 39704172 DOI: 10.1172/jci.insight.178535
Abstract

KRAS mutations are frequent in various human cancers. The development of selective inhibitors targeting KRAS mutations has opened a new era for targeted therapy. However, intrinsic and acquired resistance to these inhibitors remains a major challenge. Here, we found that Cancer cells resistant to KRAS G12C inhibitors also display cross-resistance to Other targeted therapies, such as inhibitors of RTKs or SHP2. Transcriptomic analyses revealed that the Hippo-YAP/TAZ pathway is activated in intrinsically resistant and acquired-resistance cells. Constitutive activation of YAP/TAZ conferred resistance to KRAS G12C inhibitors, while knockdown of YAP/TAZ or TEADs sensitized resistant cells to these inhibitors. This scenario was also observed in KRAS G12D-mutant Cancer cells. Mechanistically, YAP/TAZ protects cells from KRAS inhibitor-induced Apoptosis by downregulating the expression of proapoptotic genes such as BMF, BCL2L11, and PUMA, and YAP/TAZ reverses KRAS inhibitor-induced proliferation retardation by activating the SLC7A5/mTORC1 axis. We further demonstrated that dasatinib and MYF-03-176 notably enhance the efficacy of KRAS inhibitors by reducing Src kinase activity and TEAD activity. Overall, targeting the Hippo-YAP/TAZ pathway has the potential to overcome resistance to KRAS inhibitors.

Keywords

Apoptosis survival pathways; Drug screens; Drug therapy; Oncology; Therapeutics.

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