{"doi":"10.17615/73y8-rn80","title":"Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma","abstract":"Melanoma resistant to MAPK inhibitor(s) (MAPKi) displays loss-of-fitness upon experimental MAPKi withdrawal and, clinically, may be re-sensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi-addiction in MAPKi-resistant MUTBRAF or MUTNRAS melanoma. MAPKi-addiction phenotypes evident upon drug-withdrawal spanned transient cell-cycle slow-down to cell-death responses, the latter of which required a robust p-ERK rebound. Generally, drug withdrawal-induced p-ERK rebound up-regulated p38-FRA1-JUNB-CDKN1A and down-regulated proliferation, but only a robust p-ERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi-addiction across-the-board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant MUTNRAS or atypical MUTBRAF melanoma, treatment with a type I RAF inhibitor intensified p-ERK rebound elicited by MEKi-withdrawal, thereby promoting a cell-death predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi-addiction.","journal":"UNC Libraries","year":2020,"id":110246,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":487122,"name":"Gatien Moriceau","orcid":"0000-0003-3904-7669","position":1,"is_corresponding":false},{"id":266371,"name":"Robert Damoiseaux","orcid":"0000-0002-7611-7534","position":2,"is_corresponding":false},{"id":54178,"name":"Roger S. Lo","orcid":"0000-0002-5337-5004","position":3,"is_corresponding":false},{"id":525151,"name":"Lu Sun","orcid":"0000-0002-1695-3872","position":4,"is_corresponding":false},{"id":525152,"name":"Aayoung Hong","orcid":"0000-0003-0480-4973","position":5,"is_corresponding":false},{"id":267512,"name":"Sheri L. Holmen","orcid":"0000-0002-6411-6032","position":6,"is_corresponding":false},{"id":525153,"name":"Shirley H. Lomeli","orcid":"0000-0002-0872-8309","position":7,"is_corresponding":false},{"id":85400,"name":"Norman E. Sharpless","orcid":"0000-0001-7078-9455","position":8,"is_corresponding":false},{"id":525154,"name":"Marco Piva","orcid":"0000-0001-6906-6065","position":9,"is_corresponding":false},{"id":271850,"name":"Willy Hugo","orcid":"0000-0002-1426-7190","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:12:57.988348Z","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":[]}