Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation

Abstract

Vemurafenib has been developed to target common BRAF mutation V600E. It also exerts activity towards some but not all rare BRAF substitutions. Proper cataloguing of drug-sensitive and -insensitive rare mutations remains a challenge, due to low occurrence of these events and inability of commercial PCR-based diagnostic kits to detect the full spectrum of BRAF gene lesions. We considered the results of BRAF exon 15 testing in 1872 consecutive melanoma patients. BRAF mutation was identified in 1,090 (58.2%) cases. While drug-sensitive codon 600 substitutions constituted the majority of BRAF gene lesions (V600E: 962 [51.4%]; V600K: 86 [4.6%]; V600R: 17 [0.9%]), the fourth common BRAF allele was K601E accounting for 9 (0.5%) melanoma cases. The data on BRAF inhibitor sensitivity of tumors with K601E substitution are scarce. We administered single-agent vemurafenib to a melanoma patient carrying BRAF K601E mutation as the first-line treatment. Unfortunately, this therapy did not result in a tumor response. Taken together with already published data, this report indicates lack of benefit from conventional BRAF inhibitors in patients with BRAF K601E mutated melanoma.

DNA Sequencing of CD138 Cell Population Reveals TP53 and RAS-MAPK Mutations in Multiple Myeloma at Diagnosis

“…Even if it is not associated with MM (according to the ClinVar Database), K601E occurs in at least 1% of melanoma and adenocarcinoma [28][29][30]. It is associated with high kinase activity by its interaction with the phosphate-binding loop, and it could also increase the activity of the downstream MAPK pathway [31].…”

Acetylation-dependent regulation of BRAF oncogenic function

“…It is noteworthy that melanoma patients with BRAF K601E mutation failed to respond to dabrafenib treatment ( Moiseyenko et al, 2019 ; Voskoboynik et al, 2016 ). Consistently, studies using melanoma cell lines harboring BRAF K601E demonstrate that compared to BRAF V600E melanoma cells, BRAF K601E cells are refractory to BRAF-V600E inhibitors ( Yang et al, 2010 ).…”

Targeted Therapy in BRAF p.K601E–Driven NSCLC: Case Report and Literature Review

“…22 Indeed, among twelve cases of BRAF p.K601E-driven tumors (three NSCLC plus nine melanoma) reported so far, none responded to treatment with single-agent BRAF inhibitors. 10,20,23,24 Nonetheless, the reduced activity of BRAF inhibitors toward BRAF p.K601E could still have clinical impact in combination treatments. This is suggested by a patient-derived murine xenograft model of p.K601E-mutant melanoma, in which the combination of trametinib and dabrafenib was superior to trametinib monotherapy with respect to tumor volume reduction and duration of response.…”