The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAF^V600E melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF mutant melanoma and a therapeutic option for NRAS-driven and immunotherapy-resistant tumors.

中文翻译：

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综合应激反应的激活导致黑色素瘤中针对线粒体核糖体的抗生素的脆弱性


适应环境压力（包括治疗性损伤）的能力有助于肿瘤的进化和耐药性。在次优条件下，综合应激反应（ISR）通过抑制细胞质翻译来促进生存。我们发现，ISR 依赖性生存还依赖于线粒体蛋白质合成的伴随上调，这是一个可以利用线粒体糖体靶向抗生素来利用的漏洞。因此，此类药物对 MAPK 抑制敏感，从而防止 BRAF ^V600E黑色素瘤模型产生耐药性。此外，这种治疗会损害黑色素瘤的生长，而黑色素瘤表现出 ISR 活性升高以及对免疫疗法和靶向治疗的抵抗力。与此相一致的是，ISR 的药理学失活或 ATF4 的沉默可以挽救四环素的抗肿瘤反应。此外，接触多西环素的黑色素瘤患者对治疗耐药性病变产生了完全且持久的反应。我们的研究表明，线粒体核糖体靶向抗生素的重新利用为BRAF突变黑色素瘤的靶向治疗提供了合理的挽救策略，并为NRAS驱动的免疫治疗耐药性肿瘤提供了治疗选择。