Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer

• Published in: The Journal of clinical investigation Vol. 132; no. 13; pp. 1 - 16
• Main Authors: Nanjo, Shigeki, Wu, Wei, Karachaliou, Niki, Blakely, Collin M, Suzuki, Junji, Chou, Yu-Ting, Ali, Siraj M, Kerr, D Lucas, Olivas, Victor R, Shue, Jonathan, Rotow, Julia, Mayekar, Manasi K, Haderk, Franziska, Chatterjee, Nilanjana, Urisman, Anatoly, Yeo, Jia Chi, Skanderup, Anders J, Tan, Aaron C, Tam, Wai Leong, Arrieta, Oscar, Hosomichi, Kazuyoshi, Nishiyama, Akihiro, Yano, Seiji, Kirichok, Yuriy, Tan, Daniel S W, Rosell, Rafael, Okimoto, Ross A, Bivona, Trever G
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 01.07.2022
• Subjects: Alternative splicing; Apoptosis; Bcl-x protein; Biomarkers; Biomedical research; Cancer therapies; Datasets; Enzyme inhibitors; Epidermal growth factor receptors; Gene amplification; Hypotheses; Isoforms; Kinases; Lung cancer; Mitochondria; mRNA; Mutants; Mutation; Patients; Precision medicine; Response rates; Splicing factors; Targeted cancer therapy; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI145099.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.