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

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Résumé

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

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La notice

Revue

Journal of Clinical Oncology

Thématique

Melanoma and MAPK Pathways

Domaine

Biochemistry, Genetics and Molecular Biology

Établissements canadiens

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Organismes subventionnaires

Jonsson Comprehensive Cancer CenterUniversity of Texas MD Anderson Cancer CenterUniversity of California, Los AngelesPeter MacCallum Cancer CentrePlexxikonVanderbilt UniversityMoffitt Cancer CenterGenentechUniversity of PittsburghF. Hoffmann-La RocheVanderbilt-Ingram Cancer CenterYork UniversityUniversity of PennsylvaniaMassachusetts General HospitalGlaxoSmithKline

Mots-clés

VemurafenibMedicineNeuroblastoma RAS viral oncogene homologMAPK/ERK pathwayCancer researchMelanomaKinasePhosphorylationInternal medicineCancerMetastatic melanomaKRASBiologyColorectal cancerCell biology

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