Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRAS<sup>MUT</sup>melanoma
ABSTRACT Although oncogenic NRAS activates MAPK signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant tumors. Here we report that silencing the ribosomal protein S6 kinase 2 (S6K2), while preserving the activity of S6K1, perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces ER stress, and PPARα activation, triggering cell death selectively in MAPKi-resistant melanoma. We show that combining PPARα agonists and polyunsaturated fatty acids phenocopies the effects of S6K2 abrogation, blocking tumor growth in PDX and immunocompetent mouse pre-clinical models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRAS-mutant melanoma that are resistant to global MAPK pathway inhibitors.One Sentence Summary S6K2 is a vulnerability in MAPK inhibitor-resistant NRAS-mutant melanoma.
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 18. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lipchick, Brittany [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2021.04.07.438684 |
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| PPN (Katalog-ID): |
XBI02031342X |
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| 245 | 1 | 0 | |a Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRAS<sup>MUT</sup>melanoma |
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| 520 | |a ABSTRACT Although oncogenic NRAS activates MAPK signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant tumors. Here we report that silencing the ribosomal protein S6 kinase 2 (S6K2), while preserving the activity of S6K1, perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces ER stress, and PPARα activation, triggering cell death selectively in MAPKi-resistant melanoma. We show that combining PPARα agonists and polyunsaturated fatty acids phenocopies the effects of S6K2 abrogation, blocking tumor growth in PDX and immunocompetent mouse pre-clinical models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRAS-mutant melanoma that are resistant to global MAPK pathway inhibitors.One Sentence Summary S6K2 is a vulnerability in MAPK inhibitor-resistant NRAS-mutant melanoma | ||
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| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Guterres, Adam N. |e verfasserin |0 (orcid)0000-0002-4607-2099 |4 aut | |
| 700 | 1 | |a Chen, Hsin-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Zundell, Delaine M. |e verfasserin |4 aut | |
| 700 | 1 | |a Aguila, Segundo Del |e verfasserin |4 aut | |
| 700 | 1 | |a Reyes-Uribe, Patricia I. |e verfasserin |4 aut | |
| 700 | 1 | |a Basu, Subhasree |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Xiangfan |e verfasserin |4 aut | |
| 700 | 1 | |a Kossenkov, Andrew V. |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Yiling |e verfasserin |4 aut | |
| 700 | 1 | |a Mills, Gordon B. |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Goldman, Aaron R. |e verfasserin |4 aut | |
| 700 | 1 | |a Murphy, Maureen E. |e verfasserin |4 aut | |
| 700 | 1 | |a Speicher, David W. |e verfasserin |4 aut | |
| 700 | 1 | |a Villanueva, Jessie |e verfasserin |0 (orcid)0000-0001-5701-2609 |4 aut | |
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