ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
©2023 American Association for Cancer Research..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:83 |
|---|---|
| Enthalten in: |
Cancer research - 83(2023), 7 vom: 04. Apr., Seite 1128-1146 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Eichhoff, Ossia M [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 05.04.2023 Date Revised 06.07.2023 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1158/0008-5472.CAN-22-1826 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM354520083 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM354520083 | ||
| 003 | DE-627 | ||
| 005 | 20231226062412.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/0008-5472.CAN-22-1826 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1181.xml |
| 035 | |a (DE-627)NLM354520083 | ||
| 035 | |a (NLM)36946761 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Eichhoff, Ossia M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.04.2023 | ||
| 500 | |a Date Revised 06.07.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins B-raf |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.12.2 |2 NLM | |
| 650 | 7 | |a NRAS protein, human |2 NLM | |
| 650 | 7 | |a EC 3.6.1.- |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a GTP Phosphohydrolases |2 NLM | |
| 650 | 7 | |a EC 3.6.1.- |2 NLM | |
| 700 | 1 | |a Stoffel, Corinne I |e verfasserin |4 aut | |
| 700 | 1 | |a Käsler, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Briker, Luzia |e verfasserin |4 aut | |
| 700 | 1 | |a Turko, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Karsai, Gergely |e verfasserin |4 aut | |
| 700 | 1 | |a Zila, Nina |e verfasserin |4 aut | |
| 700 | 1 | |a Paulitschke, Verena |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Phil F |e verfasserin |4 aut | |
| 700 | 1 | |a Leitner, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Bileck, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Zamboni, Nicola |e verfasserin |4 aut | |
| 700 | 1 | |a Irmisch, Anja |e verfasserin |4 aut | |
| 700 | 1 | |a Balazs, Zsolt |e verfasserin |4 aut | |
| 700 | 1 | |a Tastanova, Aizhan |e verfasserin |4 aut | |
| 700 | 1 | |a Pascoal, Susana |e verfasserin |4 aut | |
| 700 | 1 | |a Johansen, Pål |e verfasserin |4 aut | |
| 700 | 1 | |a Wegmann, Rebekka |e verfasserin |4 aut | |
| 700 | 1 | |a Mena, Julien |e verfasserin |4 aut | |
| 700 | 1 | |a Othman, Alaa |e verfasserin |4 aut | |
| 700 | 1 | |a Viswanathan, Vasanthi S |e verfasserin |4 aut | |
| 700 | 1 | |a Wenzina, Judith |e verfasserin |4 aut | |
| 700 | 1 | |a Aloia, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Saltari, Annalisa |e verfasserin |4 aut | |
| 700 | 1 | |a Dzung, Andreas |e verfasserin |4 aut | |
| 700 | 0 | |a TuPro Consortium |e verfasserin |4 aut | |
| 700 | 1 | |a Krauthammer, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Schreiber, Stuart L |e verfasserin |4 aut | |
| 700 | 1 | |a Hornemann, Thorsten |e verfasserin |4 aut | |
| 700 | 1 | |a Distel, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Snijder, Berend |e verfasserin |4 aut | |
| 700 | 1 | |a Dummer, Reinhard |e verfasserin |4 aut | |
| 700 | 1 | |a Levesque, Mitchell P |e verfasserin |4 aut | |
| 700 | 1 | |a Aebersold, Rudolf |e investigator |4 oth | |
| 700 | 1 | |a Ak, Melike |e investigator |4 oth | |
| 700 | 1 | |a Al-Quaddoomi, Faisal S |e investigator |4 oth | |
| 700 | 1 | |a Albert, Silvana I |e investigator |4 oth | |
| 700 | 1 | |a Albinus, Jonas |e investigator |4 oth | |
| 700 | 1 | |a Alborelli, Ilaria |e investigator |4 oth | |
| 700 | 1 | |a Andani, Sonali |e investigator |4 oth | |
| 700 | 1 | |a Attinger, Per-Olof |e investigator |4 oth | |
| 700 | 1 | |a Bacac, Marina |e investigator |4 oth | |
| 700 | 1 | |a Baumhoer, Daniel |e investigator |4 oth | |
| 700 | 1 | |a Beck-Schimmer, Beatrice |e investigator |4 oth | |
| 700 | 1 | |a Beerenwinkel, Niko |e investigator |4 oth | |
| 700 | 1 | |a Beisel, Christian |e investigator |4 oth | |
| 700 | 1 | |a Bernasconi, Lara |e investigator |4 oth | |
| 700 | 1 | |a Bodenmiller, Bernd |e investigator |4 oth | |
| 700 | 1 | |a Bonilla, Ximena |e investigator |4 oth | |
| 700 | 1 | |a Bosshard, Lars |e investigator |4 oth | |
| 700 | 1 | |a Calgua, Byron |e investigator |4 oth | |
| 700 | 1 | |a Casanova, Ruben |e investigator |4 oth | |
| 700 | 1 | |a Chevrier, Stéphane |e investigator |4 oth | |
| 700 | 1 | |a Chicherova, Natalia |e investigator |4 oth | |
| 700 | 1 | |a Coelho, Ricardo |e investigator |4 oth | |
| 700 | 1 | |a D'Costa, Maya |e investigator |4 oth | |
| 700 | 1 | |a Danenberg, Esther |e investigator |4 oth | |
| 700 | 1 | |a Davidson, Natalie |e investigator |4 oth | |
| 700 | 1 | |a Drăgan, Monica-Andreea |e investigator |4 oth | |
| 700 | 1 | |a Dummer, Reinhard |e investigator |4 oth | |
| 700 | 1 | |a Engler, Stefanie |e investigator |4 oth | |
| 700 | 1 | |a Erkens, Martin |e investigator |4 oth | |
| 700 | 1 | |a Eschbach, Katja |e investigator |4 oth | |
| 700 | 1 | |a Esposito, Cinzia |e investigator |4 oth | |
| 700 | 1 | |a Fedier, André |e investigator |4 oth | |
| 700 | 1 | |a Ferreira, Pedro |e investigator |4 oth | |
| 700 | 1 | |a Ficek, Joanna |e investigator |4 oth | |
| 700 | 1 | |a Frei, Anja L |e investigator |4 oth | |
| 700 | 1 | |a Frey, Bruno |e investigator |4 oth | |
| 700 | 1 | |a Goetze, Sandra |e investigator |4 oth | |
| 700 | 1 | |a Grob, Linda |e investigator |4 oth | |
| 700 | 1 | |a Gut, Gabriele |e investigator |4 oth | |
| 700 | 1 | |a Günther, Detlef |e investigator |4 oth | |
| 700 | 1 | |a Haberecker, Martina |e investigator |4 oth | |
| 700 | 1 | |a Haeuptle, Pirmin |e investigator |4 oth | |
| 700 | 1 | |a Heinzelmann-Schwarz, Viola |e investigator |4 oth | |
| 700 | 1 | |a Herter, Sylvia |e investigator |4 oth | |
| 700 | 1 | |a Holtackers, Rene |e investigator |4 oth | |
| 700 | 1 | |a Huesser, Tamara |e investigator |4 oth | |
| 700 | 1 | |a Immer, Alexander |e investigator |4 oth | |
| 700 | 1 | |a Irmisch, Anja |e investigator |4 oth | |
| 700 | 1 | |a Francis, Jacob |e investigator |4 oth | |
| 700 | 1 | |a Jacobs, Andrea |e investigator |4 oth | |
| 700 | 1 | |a Jaeger, Tim M |e investigator |4 oth | |
| 700 | 1 | |a Jahn, Katharina |e investigator |4 oth | |
| 700 | 1 | |a James, Alva R |e investigator |4 oth | |
| 700 | 1 | |a Jermann, Philip M |e investigator |4 oth | |
| 700 | 1 | |a Kahles, André |e investigator |4 oth | |
| 700 | 1 | |a Kahraman, Abdullah |e investigator |4 oth | |
| 700 | 1 | |a Koelzer, Viktor H |e investigator |4 oth | |
| 700 | 1 | |a Kuebler, Werner |e investigator |4 oth | |
| 700 | 1 | |a Kuipers, Jack |e investigator |4 oth | |
| 700 | 1 | |a Kunze, Christian P |e investigator |4 oth | |
| 700 | 1 | |a Kurzeder, Christian |e investigator |4 oth | |
| 700 | 1 | |a Lehmann, Kjong-Van |e investigator |4 oth | |
| 700 | 1 | |a Levesque, Mitchell |e investigator |4 oth | |
| 700 | 1 | |a Lischetti, Ulrike |e investigator |4 oth | |
| 700 | 1 | |a Lugert, Sebastian |e investigator |4 oth | |
| 700 | 1 | |a Maass, Gerd |e investigator |4 oth | |
| 700 | 1 | |a Manz, Marcus G |e investigator |4 oth | |
| 700 | 1 | |a Markolin, Philipp |e investigator |4 oth | |
| 700 | 1 | |a Mehnert, Martin |e investigator |4 oth | |
| 700 | 1 | |a Mena, Julien |e investigator |4 oth | |
| 700 | 1 | |a Metzler, Julian M |e investigator |4 oth | |
| 700 | 1 | |a Miglino, Nicola |e investigator |4 oth | |
| 700 | 1 | |a Milani, Emanuela S |e investigator |4 oth | |
| 700 | 1 | |a Moch, Holger |e investigator |4 oth | |
| 700 | 1 | |a Muenst, Simone |e investigator |4 oth | |
| 700 | 1 | |a Murri, Riccardo |e investigator |4 oth | |
| 700 | 1 | |a Ng, Charlotte KY |e investigator |4 oth | |
| 700 | 1 | |a Nicolet, Stefan |e investigator |4 oth | |
| 700 | 1 | |a Nowak, Marta |e investigator |4 oth | |
| 700 | 1 | |a Lopez, Monica Nunez |e investigator |4 oth | |
| 700 | 1 | |a Pedrioli, Patrick GA |e investigator |4 oth | |
| 700 | 1 | |a Pelkmans, Lucas |e investigator |4 oth | |
| 700 | 1 | |a Piscuoglio, Salvatore |e investigator |4 oth | |
| 700 | 1 | |a Prummer, Michael |e investigator |4 oth | |
| 700 | 1 | |a Rimmer, Natalie |e investigator |4 oth | |
| 700 | 1 | |a Ritter, Mathilde |e investigator |4 oth | |
| 700 | 1 | |a Rommel, Christian |e investigator |4 oth | |
| 700 | 1 | |a Rosano-González, María L |e investigator |4 oth | |
| 700 | 1 | |a Rätsch, Gunnar |e investigator |4 oth | |
| 700 | 1 | |a Santacroce, Natascha |e investigator |4 oth | |
| 700 | 1 | |a Sarabia del Castillo, Jacobo |e investigator |4 oth | |
| 700 | 1 | |a Schlenker, Ramona |e investigator |4 oth | |
| 700 | 1 | |a Schwalie, Petra C |e investigator |4 oth | |
| 700 | 1 | |a Schwan, Severin |e investigator |4 oth | |
| 700 | 1 | |a Schär, Tobias |e investigator |4 oth | |
| 700 | 1 | |a Senti, Gabriela |e investigator |4 oth | |
| 700 | 1 | |a Shao, Wenguang |e investigator |4 oth | |
| 700 | 1 | |a Singer, Franziska |e investigator |4 oth | |
| 700 | 1 | |a Sivapatham, Sujana |e investigator |4 oth | |
| 700 | 1 | |a Snijder, Berend |e investigator |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer research |d 1945 |g 83(2023), 7 vom: 04. Apr., Seite 1128-1146 |w (DE-627)NLM000001740 |x 1538-7445 |7 nnns |
| 773 | 1 | 8 | |g volume:83 |g year:2023 |g number:7 |g day:04 |g month:04 |g pages:1128-1146 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/0008-5472.CAN-22-1826 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 83 |j 2023 |e 7 |b 04 |c 04 |h 1128-1146 | ||