{"doi":"10.1101/2021.04.07.438684","title":"Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRAS <sup>MUT</sup> melanoma","abstract":"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","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223793,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":825594,"name":"Adam N. Guterres","orcid":"0000-0002-4607-2099","position":1,"is_corresponding":false},{"id":825595,"name":"Hsin‐Yi Chen","orcid":"0009-0003-7567-9935","position":2,"is_corresponding":false},{"id":825971,"name":"Delaine M. Zundell","orcid":null,"position":3,"is_corresponding":false},{"id":825972,"name":"Segundo Del Aguila","orcid":null,"position":4,"is_corresponding":false},{"id":825973,"name":"Patricia Reyes-Uribe","orcid":null,"position":5,"is_corresponding":false},{"id":384313,"name":"Subhasree Basu","orcid":null,"position":6,"is_corresponding":false},{"id":493040,"name":"Xiangfan Yin","orcid":null,"position":7,"is_corresponding":false},{"id":245076,"name":"Andrew V. Kossenkov","orcid":"0000-0002-1536-0418","position":8,"is_corresponding":false},{"id":13753,"name":"Yiling Lu","orcid":"0000-0002-3662-2106","position":9,"is_corresponding":false},{"id":13817,"name":"Gordon B. Mills","orcid":"0000-0002-0144-9614","position":10,"is_corresponding":false},{"id":245077,"name":"Qin Liu","orcid":"0000-0001-9964-580X","position":11,"is_corresponding":false},{"id":241838,"name":"Aaron R. Goldman","orcid":"0000-0001-7605-9592","position":12,"is_corresponding":false},{"id":348573,"name":"Maureen E. Murphy","orcid":"0000-0001-7644-7296","position":13,"is_corresponding":false},{"id":258005,"name":"David W. Speicher","orcid":"0000-0003-1311-4261","position":14,"is_corresponding":false},{"id":621838,"name":"Jessie Villanueva","orcid":"0000-0001-5701-2609","position":15,"is_corresponding":false},{"id":825593,"name":"Brittany C. Lipchick","orcid":"0000-0002-7326-0079","position":0,"is_corresponding":true}],"reference_count":104,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:14.760456Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}