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

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 7

Resistance caused by RBM10 deficiency in EGFR-mutant lung cancer can be overcome with Bcl-xL and EGFR inhibitor combination therapy.

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Resistance caused by RBM10 deficiency in EGFR-mutant lung cancer can be ...
(A–F) RBM10-deficient A014 (EGFR L858R; RBM10 Q255*) and H1975 (EGFR L8585R/T790M; RBM10 G840fs*7) cells were treated with 500 nM navitoclax (ABT-263) alone or in combination with the indicated osimertinib concentrations. (A and B) Crystal violet viability assays were performed, and (C–F) apoptosis was measured according to PARP cleavage and caspase 3/-7 activity. (E and F) Each bar represents the mean ± SEM of the FC after normalization to the DMSO control. (G and H) Western blot analysis of Bcl-xL KD with siRNA in combination with 500 nM osimertinib in A014 and H1975 cells. (I) Mice bearing H1975 subcutaneous xenografts were treated with vehicle, navitoclax (50 mg/kg), osimertinib (5 mg/kg), or their combination (navitoclax plus osimertinib) for 14 days (n = 10 tumors in each group). The percentage of change in tumor volume compared with baseline for individual xenografts is shown. (J) H1975 xenograft tumor explants were treated with vehicle, navitoclax, osimertinib, or their combination (navitoclax plus osimertinib at 50 mg/kg and 5 mg/kg, respectively) for 4 days. One tumor of representative size from each group was harvested 4 hours after treatment on day 5, and the indicated protein levels were determined by Western blot analysis. Data represent 3 independent experiments. *P < 0.05, by 1-way ANOVA.