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 BRAFV600E 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.

Cancer Research Centre of Toulouse Institut national de la santé et de la recherche médicale Joint Research Unit 1037 Toulouse France

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of General Medical Oncology Leuven Cancer Institute Universitair Ziekenhuis Leuven Leuven Belgium

Department of Oncology Laboratory for Molecular Cancer Biology Katholieke Universiteit Leuven Belgium

Laboratoire d'Excellence TOUCAN Toulouse France

Laboratory for Molecular Cancer Biology Center for Cancer Biology Vlaams Instituut voor Biotechnologie Leuven Belgium

Laboratory for RNA Cancer Biology Department of Oncology Katholieke Universiteit Leuven Leuven Belgium

Laboratory of RNA Regulatory Networks Department of Cellular Computational and Integrative Biology University of Trento Trento Italy

Taconic Biosciences Leverkusen Germany

Trace Leuven Cancer Institute Katholieke Universiteit Leuven Belgium

Translational Cell and Tissue Research Katholieke Universiteit Leuven Belgium

Université Toulouse 3 Paul Sabatier Toulouse France

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Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma