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.
Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
Disclosures: R. Vendramin and E. Leucci reported a patent to PCT/EP2020/059416 pending "UVEAL MELANOMA TREATMENT." E. Leucci reported non-financial support from Taconic Biosciences during the conduct of the study. I. Gladwyn-Ng is an employee of Taconic Biosciences. No other disclosures were reported.
- Award Id(s): 2016-054
- Award Id(s): 1S47519N
- Award Id(s): 1SD1620N
- Award Id(s): RVO 68378050,LM2018126
- Award Id(s): CZ.02.1.01/0.0/0.0/16_013/0001789
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Roberto Vendramin, Vicky Katopodi, Sonia Cinque, Angelina Konnova, Zorica Knezevic, Sara Adnane, Yvessa Verheyden, Panagiotis Karras, Ewout Demesmaeker, Francesca M. Bosisio, Lukas Kucera, Jan Rozman, Ivan Gladwyn-Ng, Lara Rizzotto, Erik Dassi, Stefania Millevoi, Oliver Bechter, Jean-Christophe Marine, Eleonora Leucci; Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma. J Exp Med 6 September 2021; 218 (9): e20210571. doi: https://doi.org/10.1084/jem.20210571
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