Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms.

摘要: Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide accelerate development, we characterized responses five patient derived xenograft models treated with Vemurafenib. Three BRAFV600E showed acquired resistance, one model had a complete durable response, BRAFV600V was expectedly unresponsive. In progressing tumors, variety of mechanisms to BRAF inhibition were uncovered, including mutant alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, increased gene amplification copy number. The among the similar pathways identified in specimens from patients on inhibitor therapy. addition, there both inter- intra-patient heterogeneity mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy Vemurafenib-resistant tumors caused toxicity resistance. However, eradicated when Vemurafenib combined inhibitor. diversity models; distinct resistance; ability overcome addition provide scheduling rationale trials next-generation combinations.