Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.
Aged
Animals
Antibiotics, Antineoplastic
/ pharmacology
Cell Line, Tumor
Doxycycline
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
Female
Humans
Male
Melanoma
/ drug therapy
Mice, Inbred C57BL
Mice, Nude
Mitochondrial Ribosomes
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Stress, Physiological
/ drug effects
Tigecycline
/ pharmacology
Uveal Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
06 09 2021
06 09 2021
Historique:
received:
10
03
2021
revised:
10
05
2021
accepted:
16
06
2021
entrez:
21
7
2021
pubmed:
22
7
2021
medline:
25
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34287642
pii: 212494
doi: 10.1084/jem.20210571
pmc: PMC8424468
pii:
doi:
Substances chimiques
Antibiotics, Antineoplastic
0
Protein Kinase Inhibitors
0
Tigecycline
70JE2N95KR
Doxycycline
N12000U13O
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021 Vendramin et al.
Déclaration de conflit d'intérêts
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.
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