biostudies-literatureVendramin RStichting Tegen KankerKom op tegen KankerCzech Academy of SciencesEuroPDX ConsortiumAmanda and Jonathan EilianKU LeuvenMelanoma Research AllianceResearch Foundation – FlandersMinistry of Education, Youth and SportsFlemish Cancer SocietyEuropean Structural and Investment Fundse20210571https://www.ebi.ac.uk/biostudies/studies/S-EPMC8424468biostudies-literatureUnknown218(9)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 silenThe Journal of experimental medicineActivation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.PMC84244682016-054LM2018126CZ.02.1.01/0.0/0.0/16_013/0001789RVO 683780501S47519N1SD1620NMarine JCRizzotto LKucera LDemesmaeker ELeucci EBechter OKarras PDassi EGladwyn-Ng IVerheyden YCinque SMillevoi SKatopodi VKonnova ARozman JVendramin RKnezevic ZBosisio FMAdnane SfalseActivation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.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 silen2021-01-01T00:00:00Z2021 Sep2026-05-30T15:49:45.14Z2025-04-04T10:01:42.465ZS-EPMC84244683428764210.1084/jem.20210571