Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-07-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI145099 |
| _version_ | 1818549277379526656 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shigeki Nanjo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T08:31:15Z |
| format | Article |
| id | doaj.art-2ab24c64ef0a4efabc727bb6d4218018 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T08:31:15Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-2ab24c64ef0a4efabc727bb6d42180182022-12-22T00:31:05ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-07-0113213Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancerShigeki NanjoWei WuNiki KarachaliouCollin M. BlakelyJunji SuzukiYu-Ting ChouSiraj M. AliD. Lucas KerrVictor R. OlivasJonathan ShueJulia RotowManasi K. MayekarFranziska HaderkNilanjana ChatterjeeAnatoly UrismanJia Chi YeoAnders J. SkanderupAaron C. TanWai Leong TamOscar ArrietaKazuyoshi HosomichiAkihiro NishiyamaSeiji YanoYuriy KirichokDaniel S.W. TanRafael RosellRoss A OkimotoTrever G. BivonaMolecularly 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.https://doi.org/10.1172/JCI145099OncologyTherapeutics |
| spellingShingle | 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 Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer The Journal of Clinical Investigation Oncology Therapeutics |
| title | Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer |
| title_full | Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer |
| title_fullStr | Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer |
| title_full_unstemmed | Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer |
| title_short | Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer |
| title_sort | deficiency of the splicing factor rbm10 limits egfr inhibitor response in egfr mutant lung cancer |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/JCI145099 |
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