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Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma
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SYSNO ASEP 0555718 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma Author(s) Vendramin, R. (BE)
Katopodi, V. (BE)
Cinque, S. (BE)
Konnova, A. (BE)
Knezevic, Z. (BE)
Adnane, S. (BE)
Verheyden, Y. (BE)
Karras, P. (BE)
Demesmaeker, E. (BE)
Bosisio, F. (BE)
Kučera, Lukáš (UMG-J)
Rozman, Jan (UMG-J)
Gladwyn-Ng, I. (DE)
Rizzotto, L. (BE)
Dassi, E. (IT)
Millevoi, S. (FR)
Bechter, O. (BE)
Marine, J. (BE)
Leucci, E. (BE)Number of authors 19 Article number e20210571 Source Title Journal of Experimental Medicine. - : Rockefeller University Press - ISSN 0022-1007
Roč. 218, č. 9 (2021)Number of pages 27 s. Publication form Online - E Language eng - English Country US - United States Keywords mitochondrial translation ; drug-tolerant ; cancer ; resistance ; metabolism ; atf4 ; dysfunction ; doxycycline ; transition ; microbiome Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001789 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure CCP II - 90126 - Ústav molekulární genetiky AV ČR, v. v. i. Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000704364600005 DOI 10.1084/jem.20210571 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2022 Electronic address https://rupress.org/jem/article/218/9/e20210571/212494/Activation-of-the-integrated-stress-response
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