{"doi":"10.1200/po.23.00260","title":"Evolution of Rapid Clonal Dynamics and Non–Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer","abstract":"PURPOSE: Combined BRAF, MEK, and EGFR inhibition can induce clinical responses in BRAF-V600E-mutant colon cancer, but rapid resistance often occurs. METHODS: We use serial monitoring of circulating tumor DNA cell-free plasma DNA (cfDNA) in a patient case study in addition to organoids derived from mouse models of BRAF-V600E-mutant intestinal cancer, which emulated the patient's mutational profile to assess drug treatment efficacy. RESULTS: We demonstrate dynamic evolution of resistance to combined EGFR/BRAF/MEK inhibition in a pediatric patient with metastatic BRAF-V600E-mutant, mismatch repair-stable colon cancer. Initial resistance to targeted therapy was associated with development of MET amplification. Sequential treatment with chemotherapy and targeted therapy resulted in clearing of the resistant MET-amplified clone. Rechallenge with combined BRAF/EGFR inhibition resulted in clinical and radiographic response, demonstrating these treatments may be non-cross-resistant. Tumor organoids were used to model clinical findings and demonstrated effectiveness of combined targeted therapy and chemotherapy. CONCLUSION: These findings suggest rational strategies for combining sequential chemotherapy and BRAF-/EGFR-directed therapy in BRAF-V600E-mutant colon cancer to prevent resistance and improve outcome. The data demonstrate rapid clonal dynamics in response to effective therapies in BRAF-V600E-mutant colon cancer that can be monitored by serial cfDNA analysis. Moreover, in mismatch repair-proficient BRAF-V600E-mutant colon cancers, combined EGFR and BRAF/MEK therapy is not cross-resistant with standard chemotherapy, suggesting new rational combination treatment strategies.","journal":"JCO Precision Oncology","year":2024,"id":449662,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"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":1151366,"name":"Jillian N. 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Höchster","orcid":"0000-0002-9893-1529","position":13,"is_corresponding":false},{"id":425699,"name":"Janice M. Mehnert","orcid":"0000-0001-9492-9264","position":14,"is_corresponding":false},{"id":589793,"name":"Gregory Riedlinger","orcid":"0000-0001-5690-7777","position":15,"is_corresponding":false},{"id":491652,"name":"Hossein Khiabanian","orcid":"0000-0003-1446-4394","position":16,"is_corresponding":false},{"id":241177,"name":"Michael P. 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