Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer
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
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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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 3

RBM10 deficiency limits the therapeutic efficacy of EGFR TKIs.

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RBM10 deficiency limits the therapeutic efficacy of EGFR TKIs. (A and B)...
(A and B) Waterfall plots representing immunodeficient mice bearing H3255 (A) or PC-9 (B) tumor xenografts expressing either shScr control or shRBM10. Mice were treated with 2 mg/kg (H3255) or 5 mg/kg (PC-9) osimertinib once daily over 14 days (n = 10 tumors per treatment cohort). Percentage changes in tumor volume compared with baseline volume (day 0) for individual tumor xenografts are shown. (C and D) H3255 and PC-9 tumor xenograft explants demonstrating the effect of RBM10 KD on PARP cleavage in mice treated with osimertinib or vehicle for 14 days. One tumor of representative size from each group was harvested 4 hours after the indicated treatments on day 15, and subsequent analyses of the indicated proteins was performed by Western blotting. (E–G) PC-9 cells expressing either shScr or shRBM10 in a validated orthotopic lung tumor model were treated with 5 mg/kg osimertinib once daily for 60 days. Representative bioluminescence images (E) and mean relative photon flux (F) are shown. *P < 0.05. (G) PFS comparing the PC-9 shScr control and PC-9 shRBM10 mice (P = 0.0002, Wilcoxon test).