Dual Mutations No Obstacle to Targeted Melanoma Therapy

Roger Lo, MD, PhD

Assistant Professor Dermatology, Molecular Medicine and Pharmacology University of California, Los Angeles, CA

Concurrent mutations in MEK1 and BRAF genes do not confer resistance to BRAF inhibitors in advanced melanoma, contrary to what investigators had expected to find when they launched a study of genetic sequencing tissue samples.

Tumor samples from five patients with melanoma harbored mutations in both MEK1 and BRAF genes. Yet, three of the five patients had objective responses during treatment with a BRAF inhibitor.

The observation defied expectations and offered an illustration of why scientists should keep an open mind and not be guided by what they expect to happen, Roger Lo, MD, PhD, said during a press briefing at the American Association for Cancer Research Annual Meeting held in March/ April in Chicago, Illinois.

“We expected that this second mutation was involved in drug resistance, and it wasn’t,” said Lo. “We also expected that only one mutation would exist in this signaling pathway, and that was also wrong.”

More than 50% of patients with advanced melanoma have tumors that harbor BRAF mutations. Clinical experience with the BRAF inhibitors vemurafenib (Zelboraf) and dabrafenib has shown that about 60% of BRAF-mutant tumors respond to the treatment. The remaining mutation-carrying tumors are presumed resistant, and acquired resistance to BRAF inhibitors is a fairly common occurrence, said Lo.

A missense activating mutation in MEK1 exon 3 has been proposed as one possible mechanism for resistance to BRAF inhibitors. However, somatic-activating MEK1/2 mutations are thought to be rare in human tumors.

To examine the potential role of mutant MEK1/2 in BRAF inhibitor resistance, Lo and colleagues examined tumor specimens from 31 patients with BRAF-mutant advanced melanoma treated with a BRAF inhibitor. For each patient, pre- and posttreatment specimens were available for comparison.

This illustration portrays the mechanism of action of vemurafenib (Zelboraf) in inhibiting BRAF activity.

Illustration courtesy of Genentech, a member of the Roche Group

Defying the investigators’ expectations, five of the 31 tumors exhibited concurrent mutations in MEK1 exon 3 and BRAF. No tumor specimens had MEK2 exon 3 mutations. Among 18 patients with acquired resistance to BRAF inhibitors, MEK1 exon 3 mutations were found only in tumors that had pre-existing BRAF/MEK1 mutations at baseline.

The presence of concurrent mutations did not significantly affect mean progression-free survival (182.4 days in patients with wild-type MEK1 vs 114 days with mutant MEK1 melanoma; 2-tailed P = .09). Mean best overall response also did not differ significantly between patients with wild-type MEK1 (50%) or mutant MEK1 (41.6%; 2-tailed P = .45).

A series of confirmatory in vitro studies also revealed no evidence of an adverse impact of MEK1 mutations on BRAF-mutated tumor cells’ response to BRAF inhibitors.

Alluding to ongoing clinical evaluation of combined BRAF/MEK inhibitors, Lo and coauthors of the Cancer Discovery article noted that early data “showing preliminary safety and a high response rate of BRAF-mutant melanomas suggest improved durability of clinical response (compared with single-agent therapy).”

Shi H, Moriceau G, Kong X, et al. Preexisting MEK1 exon 3 mutations in ^V600E/K BRAF melanomas do not confer resistance to BRAF inhibitors [published online ahead of print April 1, 2012]. Cancer Discov. 2012; 2(5):414-424. doi: 10.1158/2159-8290.CD-12-0022.