Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer
Shigeki Nanjo, … , Ross A Okimoto, Trever G. Bivona
Shigeki Nanjo, … , Ross A Okimoto, Trever G. Bivona
Published May 17, 2022
Citation Information: J Clin Invest. 2022;132(13):e145099. https://doi.org/10.1172/JCI145099.
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Research Article Oncology Therapeutics

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

Abstract

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.

Authors

Shigeki Nanjo, Wei Wu, Niki Karachaliou, Collin M. Blakely, Junji Suzuki, Yu-Ting Chou, Siraj M. Ali, D. Lucas Kerr, Victor R. Olivas, Jonathan Shue, Julia Rotow, Manasi K. Mayekar, Franziska Haderk, Nilanjana Chatterjee, Anatoly Urisman, Jia Chi Yeo, Anders J. Skanderup, Aaron C. Tan, Wai Leong Tam, Oscar Arrieta, Kazuyoshi Hosomichi, Akihiro Nishiyama, Seiji Yano, Yuriy Kirichok, Daniel S.W. Tan, Rafael Rosell, Ross A Okimoto, Trever G. Bivona

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Figure 2

RBM10 modulates the apoptotic response to osimertinib in EGFR-mutant LA.

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RBM10 modulates the apoptotic response to osimertinib in EGFR-mutant LA....
(A–D) H3255 and PC-9 (mutant EGFR and WT RBM10) cells expressing shRBM10 or the shScr control were treated with the third-generation EGFR inhibitor osimertinib (500 nM) or DMSO for 48–72 hours. Western blot analysis of the indicated proteins from cellular protein extracts was normalized to actin. (A and B) Quantification of cleaved PARP was determined by signal densitometry. (C and D) The apoptotic response was assessed using a Caspase-Glo 3/7 assay. Each bar represents the mean ± SEM of the FC after normalization to the DMSO control. (E and F) RBM10-deficient A014 (EGFR-mutant and RBM10 Q255*) cells with genetic reconstitution of WT RBM10 were treated with osimertinib (500 nM) for 48 hours. Western blotting of the indicated lysates was normalized to actin (E). Caspase 3/-7 activity was measured using a Caspase-Glo 3/7 assay. Each bar represents the mean ± SEM of the FC after normalization to DMSO control. (F). Data represent 3 independent experiments. *P < 0.05, by 1-way ANOVA. Osi, osimetertinib.