Pharmacodynamic Effects and Mechanisms of Resistance to Vemurafenib in Patients With Metastatic Melanoma

摘要: PURPOSE To assess pharmacodynamic effects and intrinsic acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding mechanism action ultimately optimization metastatic melanoma therapy. METHODS In phase II clinical study NP22657 (BRIM-2), patients received oral doses (960 mg twice per day). Serial biopsies were collected changes mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, factors causing or by immunohistochemistry, DNA sequencing, somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling progression. An association between decrease extracellular signal-related (ERK) phosphorylation objective response was observed paired (n = 22; P .013). Low expression phosphatase tensin homolog showed a modest with lower response. Baseline mutations MEK1(P124) coexisting BRAF(V600) noted seven 92 samples; their presence did not preclude tumor responses. Acquired associated reactivation as elevated ERK1/2 levels progressive lesions appearance secondary NRAS(Q61) MEK1(Q56P) MEK1(E203K) mutations. These two activating MEK1 had previously been vivo tumors. CONCLUSION inhibits proliferation oncogenic through pathway. results primarily from driven NRAS subsets patients. The data suggest that inhibition downstream should help overcome resistance.