{"doi":"10.1093/narcan/zcad061","title":"Single-cell genomics analysis reveals complex genetic interactions in an <i>in vivo</i> model of acquired BRAF inhibitor resistance","abstract":"Abstract The evolution of therapeutic resistance is a major obstacle to the success of targeted oncology drugs. While both inter- and intratumoral heterogeneity limit our ability to detect resistant subpopulations that pre-exist or emerge during treatment, our ability to analyze tumors with single-cell resolution is limited. Here, we utilized a cell-based transposon mutagenesis method to identify mechanisms of BRAF inhibitor resistance in a model of cutaneous melanoma. This screen identified overexpression of NEDD4L and VGLL3 as significant drivers of BRAF inhibitor resistance in vivo. In addition, we describe a novel single-cell genomics profiling method to genotype thousands of individual cells within tumors driven by transposon mutagenesis. This approach revealed a surprising genetic diversity among xenograft tumors and identified recurrent co-occurring mutations that emerge within distinct tumor subclones. Taken together, these observations reveal an unappreciated genetic complexity that drives BRAF inhibitor resistance.","journal":"NAR Cancer","year":2024,"id":476191,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":322043,"name":"Charlotte R. Feddersen","orcid":null,"position":1,"is_corresponding":false},{"id":1313449,"name":"Rebekah M. Peplinski","orcid":"0000-0003-0209-3151","position":2,"is_corresponding":false},{"id":1313813,"name":"Lexy S Powell","orcid":null,"position":3,"is_corresponding":false},{"id":320787,"name":"Afshin Varzavand","orcid":"0000-0001-7137-6580","position":4,"is_corresponding":false},{"id":275280,"name":"Christopher S. Stipp","orcid":"0000-0002-0828-3207","position":5,"is_corresponding":false},{"id":736310,"name":"Jesse D. Riordan","orcid":"0000-0001-6734-3954","position":6,"is_corresponding":false},{"id":320790,"name":"Adam J. Dupuy","orcid":"0000-0002-8561-4911","position":7,"is_corresponding":false},{"id":1313448,"name":"Jacob L Schillo","orcid":"0000-0002-4897-3165","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:06:25.428435Z","pmid":"38213996","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":[]}