{"doi":"10.1084/jem.20221524","title":"MYC-mediated resistance to trametinib and HCQ in PDAC is overcome by CDK4/6 and lysosomal inhibition","abstract":"Pharmacological inhibition of KRAS>RAF>MEK1/2>ERK1/2 signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of P/HCQ.","journal":"The Journal of Experimental Medicine","year":2023,"id":320183,"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":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1030688,"name":"Dilru Silva","orcid":"0000-0001-5419-1744","position":1,"is_corresponding":false},{"id":1030689,"name":"Riley Rohweder","orcid":"0000-0001-7348-1069","position":2,"is_corresponding":false},{"id":1030690,"name":"Sophia Schuman","orcid":"0000-0003-0385-9016","position":3,"is_corresponding":false},{"id":1030691,"name":"Swapna Aravind Gudipaty","orcid":"0000-0003-1050-2285","position":4,"is_corresponding":false},{"id":331299,"name":"Amanda Truong","orcid":"0000-0001-9260-5418","position":5,"is_corresponding":false},{"id":502579,"name":"Jeffrey T. Yap","orcid":"0000-0001-5306-2860","position":6,"is_corresponding":false},{"id":735360,"name":"Kajsa E. Affolter","orcid":"0000-0002-1703-0535","position":7,"is_corresponding":false},{"id":331307,"name":"Martin McMahon","orcid":"0000-0003-2812-1042","position":8,"is_corresponding":false},{"id":331302,"name":"Conan G. Kinsey","orcid":"0000-0001-5614-8627","position":9,"is_corresponding":false},{"id":1030687,"name":"Mark R. Silvis","orcid":"0000-0002-0717-1983","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:07:22.377587Z","pmid":"36719686","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":[]}