2. Academic Validation
  3. RBM10 Loss Promotes EGFR-Driven Lung Cancer and Confers Sensitivity to Spliceosome Inhibition

RBM10 Loss Promotes EGFR-Driven Lung Cancer and Confers Sensitivity to Spliceosome Inhibition

  • Cancer Res. 2023 May 2;83(9):1490-1502. doi: 10.1158/0008-5472.CAN-22-1549.
Yufang Bao # 1,  Sirui Zhang # 2,  Xiaoyu Zhang 1,  Yunjian Pan 3 4,  Yueren Yan 3 4,  Ning Wang 2,  Yunpeng Ren 1,  Ji Zuo 1,  Wei-Xing Zong 5,  Zefeng Wang 2,  Yongbo Wang 1 6
Affiliations

Affiliations

  • 1 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 2 CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 5 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey.
  • 6 Shanghai Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • # Contributed equally.
PMID: 36853175 DOI: 10.1158/0008-5472.CAN-22-1549
Abstract

In lung adenocarcinoma (LUAD), loss-of-function mutations in the splicing factor RBM10 frequently co-occur with oncogenic EGFR mutations. A detailed understanding of the functional consequences and therapeutic impact of RBM10 loss in EGFR-mutant LUAD could help identify more effective treatment strategies. Here, analysis of LUAD data sets indicated that RBM10 mutations are mutually exclusive with mutations in the tumor suppressor gene TP53. In an EGFR-driven LUAD mouse model, lung-specific ablation of either Rbm10 or Trp53 similarly promoted tumor development, leading to overlapping gene expression changes enriched in cancer-related pathways. RBM10 loss induced key RNA splicing changes concordant in mice and LUAD patients. Importantly, RBM10 deficiency conferred high sensitivity to spliceosome inhibition in EGFR-mutated LUAD cells. Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in RBM10-deficient LUAD. Together, this study establishes RBM10 as a tumor suppressor akin to p53 and provides a therapeutic strategy of targeting the splicing machinery in EGFR-driven LUAD.

Significance: Loss of the splicing factor RBM10 is mutually exclusive with p53 mutations, promotes tumorigenesis, and enhances the efficacy of spliceosome inhibition in EGFR-driven lung Cancer.

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    Description
    Target
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  • HY-15772
    99.96%, EGFR 抑制剂
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