Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer.
Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer.
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剪接因子RBM10的缺乏限制了表皮生长因子受体（EGFR）突变型肺癌对EGFR抑制剂的反应。
DOI：
10.1172/jci145099
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发表时间：
2022-07-01
期刊：
影响因子：
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通讯作者：
Bivona TG
中科院分区：
文献类型：
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作者：
Nanjo S;Wu W;Karachaliou N;Blakely CM;Suzuki J;Chou YT;Ali SM;Kerr DL;Olivas VR;Shue J;Rotow J;Mayekar MK;Haderk F;Chatterjee N;Urisman A;Yeo JC;Skanderup AJ;Tan AC;Tam WL;Arrieta O;Hosomichi K;Nishiyama A;Yano S;Kirichok Y;Tan DS;Rosell R;Okimoto RA;Bivona TG
分子靶向癌症治疗改善了具有靶向癌蛋白的癌症患者的预后，例如肺癌中的EGFR突变。然而，这些患者的长期生存仍然有限，因为治疗反应通常不完全。缺乏完全和持久的反应的一个潜在解释是，具有EGFR激活突变的癌基因驱动的癌症通常含有额外的共同发生的遗传改变。对于大多数与EGFR突变同时发生的基因改变，这一假设尚未得到验证。在这里，我们报告了与突变EGFR共同发生的mRNA剪接因子rna结合基序10 （RBM10）失活遗传改变的功能影响。RBM10缺乏降低了患者源性EGFR突变肿瘤模型中EGFR抑制剂的疗效。在治疗过程中，RBM10调节线粒体凋亡调节因子Bcl-x的mRNA选择性剪接来调节肿瘤细胞凋亡。RBM10基因失活通过降低Bcl-x的（促凋亡）Bcl-xS与（抗凋亡）Bcl-xL亚型的比例，减少了EGFR抑制剂介导的细胞凋亡。在临床样本中，RBM10缺乏是对EGFR抑制剂治疗反应不佳的生物标志物。Bcl-xL和突变EGFR的共抑制克服了RBM10缺乏引起的抗性。这项研究揭示了共同发生的遗传改变的作用，以及剪接因子缺乏对靶向激酶抑制剂癌症治疗敏感性调节的影响。
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.