{"doi":"10.3390/cancers16162914","title":"Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma","abstract":"PURPOSE: This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. RESULTS: In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose-response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. CONCLUSION: Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations.","journal":"Cancers","year":2024,"id":451679,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"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":1273570,"name":"Frances Shanahan","orcid":null,"position":1,"is_corresponding":false},{"id":856099,"name":"Logan Brooks","orcid":"0000-0003-0877-4978","position":2,"is_corresponding":false},{"id":1184182,"name":"Eva Lin","orcid":"0009-0001-6099-3847","position":3,"is_corresponding":false},{"id":1273571,"name":"Rana Mroue","orcid":null,"position":4,"is_corresponding":false},{"id":1273572,"name":"Darlene Dela Cruz","orcid":null,"position":5,"is_corresponding":false},{"id":1273082,"name":"Thomas Hunsaker","orcid":"0000-0001-7665-747X","position":6,"is_corresponding":false},{"id":1273083,"name":"Bartosz Czech","orcid":"0000-0002-9908-3007","position":7,"is_corresponding":false},{"id":473084,"name":"Purushottam D. Dixit","orcid":"0000-0003-3282-0866","position":8,"is_corresponding":false},{"id":1273573,"name":"Udi Segal","orcid":null,"position":9,"is_corresponding":false},{"id":315259,"name":"Scott E. Martin","orcid":"0000-0001-5685-9787","position":10,"is_corresponding":false},{"id":1273084,"name":"Scott A. Foster","orcid":"0000-0002-2773-7999","position":11,"is_corresponding":false},{"id":811481,"name":"Luca Gerosa","orcid":"0000-0001-6805-9410","position":12,"is_corresponding":false},{"id":1248509,"name":"Andrew Goetz","orcid":null,"position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:02:45.951080Z","pmid":"39199684","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":[]}