ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma

Author:

Eichhoff Ossia M.1ORCID,Stoffel Corinne I.1ORCID,Käsler Jan1ORCID,Briker Luzia1ORCID,Turko Patrick1ORCID,Karsai Gergely2ORCID,Zila Nina3ORCID,Paulitschke Verena3ORCID,Cheng Phil F.1ORCID,Leitner Alexander4ORCID,Bileck Andrea56ORCID,Zamboni Nicola4ORCID,Irmisch Anja1ORCID,Balazs Zsolt78ORCID,Tastanova Aizhan1ORCID,Pascoal Susana9ORCID,Johansen Pål1ORCID,Wegmann Rebekka4ORCID,Mena Julien4ORCID,Othman Alaa4ORCID,Viswanathan Vasanthi S.10ORCID,Wenzina Judith11ORCID,Aloia Andrea4ORCID,Saltari Annalisa1ORCID,Dzung Andreas1ORCID,Krauthammer Michael78ORCID,Schreiber Stuart L.10ORCID,Hornemann Thorsten2ORCID,Distel Martin9ORCID,Snijder Berend4ORCID,Dummer Reinhard1ORCID,Levesque Mitchell P.1ORCID,

Affiliation:

1. 1Department of Dermatology, University of Zurich, University Hospital Zurich, Zurich, Switzerland.

2. 2Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.

3. 3Department of Dermatology, Medical University of Vienna, Vienna, Austria.

4. 4Institute for Molecular Systems Biology, ETH Zurich, Switzerland.

5. 5Joint Metabolome Facility, Faculty of Chemistry, University of Vienna, Vienna, Austria.

6. 6Department of Analytical Chemistry, University of Vienna, Vienna, Austria.

7. 7Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.

8. 8Biomedical Informatics, University Hospital of Zurich, Zurich, Switzerland.

9. 9St. Anna Children's Cancer Research Institute, Vienna, Austria.

10. 10Broad Institute, Cambridge, Massachusetts.

11. 11Skin and Endothelium Research Division, Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Abstract

AbstractClinical 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.

Funder

Swiss National Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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