Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma.

Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Kim KB, Weber JS, Hersey P, Long GV, Lawrence D, Ott PA, Amaravadi RK, Lewis KD, Puzanov I, Lo RS, Koehler A, Kockx M, Spleiss O, Schell-Steven A, Gilbert HN, Cockey L, Bollag G, Lee RJ, Joe AK, Sosman JA, Ribas A
J Clin Oncol. 2013 31 (14): 1767-74

PMID: 23569304 · DOI:10.1200/JCO.2012.44.7888

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.

MeSH Terms (29)

Administration, Oral Adolescent Adult Aged Aged, 80 and over Antineoplastic Agents Apoptosis Cell Cycle Cell Proliferation Disease Progression Drug Resistance, Neoplasm Female GTP Phosphohydrolases Humans Immunohistochemistry Indoles Male MAP Kinase Kinase 1 MAP Kinase Signaling System Melanoma Membrane Proteins Middle Aged Mitogen-Activated Protein Kinase Kinases Point Mutation Proto-Oncogene Proteins B-raf Skin Neoplasms Sulfonamides Tumor Cells, Cultured Vemurafenib

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