MEK1 Mutation Does Not Cause BRAF Inhibitor Resistance in BRAF-Mutated Melanoma

The presence of a mutation in the MEK1 gene in melanoma patients does not cause resistance to BRAF inhibitor therapy in patients that also carry a BRAF mutation, according to a new study. Previously, experts believed that resistance to the drugs in BRAF-mutated melanoma patients could likely be blamed on the concurrent mutation in MEK1.

Slide shows a melanoma on a patient's skin

According to senior study author Roger Lo, MD, PhD, of the David Geffen School of Medicine at the University of California, Los Angeles, almost 60% of patients with BRAF-mutated melanoma initially respond to BRAF inhibitors such as vemurafenib (Zelboraf) and dabrafenib but eventually develop resistance. BRAF mutations are present in more than half of all melanomas.

“Another gene, known as MEK1, is rarely mutated in cancers, but in this study, we found to our surprise that mutated MEK1 was frequently associated with BRAF mutations,” Lo said in a press release. Lo and colleagues sequenced tumor cells in 31 patients treated with a BRAF inhibitor; 5 of these patients (16%) carried both the BRAF and MEK1 mutations.

Surprisingly, 3 of those 5 patients showed objective tumor responses to either vemurafenib or dabrafenib, consistent with the overall rate of response in melanoma populations reported in other studies.

“Based on the current state of knowledge, the presence of both mutated MEK1 and mutated BRAF is thought to be a biomarker for BRAF inhibitor resistance in melanomas,” Lo said. “However, we were surprised again when we found that patients with double BRAF/MEK1-mutated melanomas can respond to BRAF inhibitors as well as patients with single BRAF-mutated melanomas.”

The mean progression-free survival for patients with wildtype MEK1 melanoma was 182.4 days, compared with 114 days in those with mutant MEK1 tumors; this difference did not reach statistical significance (P = .09). The mean best overall response was also no different between mutant MEK1 tumors and wildtype MEK1 tumors. “The pattern of MEK1 … mutations and clinical responses could not account for either innate or acquired BRAF inhibitor resistance,” the authors wrote in the journal Cancer Discovery.

Lo and colleagues will continue to look for methods to weaken tumors with combined BRAF and MEK1 mutations, along with other indicators for BRAF inhibitor resistance. “We are pushing forward to uncover biomarkers of BRAF inhibitor sensitivity or resistance and hope to use them as a guide to formulate therapeutic strategies,” Lo said.