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| Cancer research. 2023 Mar 22. doi: 10.1158/0008-5472.CAN-22-1826. pii: 718846 |
| ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma. |
| Eichhoff OM1, Stoffel CI2, Käsler J3, Briker L4, Turko P5, Karsai G6, Zila N7, Paulitschke V8, Cheng PF9, Leitner A10, Bileck A11, Zamboni N12, Irmisch A13, Balazs Z14, Tastanova A15, Pascoal S16, Johansen P17, Wegmann R18, Mena J19, Othman A20, Viswanathan VS21, Wenzina J22, Aloia A23, Saltari A24, Dzung A25, Krauthammer M26, Schreiber SL27, Hornemann T28, Distel M29, Snijder B30, Dummer R31, Levesque MP32 |
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Abstract UNLABELLED: Clinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition. The metabolic alterations elevated baseline reactive oxygen species (ROS) levels, leading these cells to become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intratumor heterogeneity necessitates the combination of a ROS inducer and a MEK inhibitor to inhibit both tumor growth and metastasis. Ex vivo pharmacoscopy of 62 human metastatic melanomas confirmed that MEK inhibitor-resistant tumors significantly benefited from the combination therapy. Finally, oxidative stress response and translational suppression corresponded with ROS-inducer sensitivity in 486 cancer cell lines, independent of cancer type. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS inducers in melanoma and other cancers. SIGNIFICANCE: Metabolic reprogramming in drug-resistant NRAS-mutated melanoma cells confers sensitivity to ROS induction, which suppresses tumor growth and metastasis in combination with MAPK pathway inhibitors. |
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©2023 American Association for Cancer Research. |
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Publikations ID: 36946761 Quelle: öffnen |
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