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

Abstract

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.

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

“…Furthermore, NRASQ61R does not recapitulate all NRAS-driven mechanisms of resistance to BRAF inhibitors, as NRASQ61K have also been reported to be associated with an acquired resistant phenotype. 27 The focus of the current study was not on evaluating the frequency of NRASQ61R mutations in primary cutaneous melanoma, but on ascertaining the utility of a mutation-specific antibody. Therefore, our cases were not selected specifically to verify mutation rates.…”

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

“…MEK1/2 mutations, including MEK1 Q56P , have been implicated in both single-agent BRAF and combination BRAF/MEK targeting therapy-acquired resistance in patients (18,21,(34)(35)(36). Single-agent assays demonstrated that relative to the parental BRAF V600E ::MEK1 wt cells, the double-mutant BRAF V600E ::MEK1 Q56P cells displayed a markedly reduced sensitivity to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib (Fig.…”

Nras in melanoma: Targeting the undruggable target

“…RAS has been consistently described as a mechanism of resistance to BRAF inhibitors. It is well known that there is a switch in RAF isoform usage depending on whether BRAF or RAS is mutated (Table 3) [95][96][97][98][99][100][101]. In melanocytes in Table 3 Resistance to BRAF inhibitors.…”