Studies Reveal Multiple Gene Alterations Responsible for Drug Resistance in BRAF-Mutated Melanoma
Two studies using whole-exome sequencing of treatment-resistant BRAF-mutated melanomas have identified multiple gene alterations, mostly affecting the MAPK pathway. Molecularly profiling BRAF-mutated melanoma patients at the time of resistance may improve their care by tailoring combinations of targeted therapies to overcome specific resistance mechanisms, according to the research. The studies are published in Cancer Discovery.
Both studies were conducted by Levi A. Garraway, MD, PhD, Associate Professor in the Department of Medicine at the Dana-Farber Cancer Institute at Harvard Medical School in Boston, Massachusetts, and colleagues. In the first study, the researchers analyzed samples of metastatic melanomas harboring the BRAF V600E mutation taken from 45 patients who had received either vemurafenib (Zelboraf) or dabrafenib (Tafinlar). They found that 51% of the samples had multiple alternations in genes involved in the MAPK pathway, including MEK1, MEK2, and a gene regulated by the MAPK pathway called MITF. They also found multiple resistance gene alterations within the same tumor biopsy in three cases.
“Analyses of melanomas that were treated with monotherapy showed there are some genes that are commonly mutated, but there may be many other relevant genes that are less commonly mutated, a phenomenon we call a ‘long-tail distribution,’” said Dr. Garraway in a statement. “Of the resistance genes that we could characterize, the majority seemed to affect the MAPK pathway.”
Targeting Multiple Pathway Alterations
In the second study, the researchers evaluated tumor samples taken from five patients with acquired resistance to a combination therapy of dabrafenib and trametinib (Mekinist). In three of the patients, the researchers found alterations in the MAPK pathway not seen in the pretreatment tumors, including a novel activating mutation in the gene MEK2. However, the alterations found in these samples were mostly similar to those found in melanomas that developed resistance to treatment with BRAF-inhibitor monotherapy.
In follow-up laboratory studies in which melanoma cells were rendered drug-resistant, the researchers found that melanomas with resistance mutations in MEK1 or MEK2 were still sensitive to an inhibitor that acts on another component of the MAPK pathway, called ERK. This suggested that targeting ERK in addition to BRAF and MEK might be an effective approach to overcome drug-resistant melanomas with BRAF mutations.
“Drug resistance is solvable, but it is more complicated than we had initially assumed,” added Dr. Garraway. “We are hopeful that utilizing systematic approaches in partnership with large, multi-institutional clinical collaborations … will help us design new therapeutic combinations. The ultimate goal is to find new and long-lasting solutions to drug-resistant melanomas and other cancers.”
Dr. Garraway is an equity holder in Foundation Medicine; a consultant to Foundation Medicine, Novartis, Millennium/Takeda, Daiichi Sankyo, and Boehringer Ingelheim; and a recipient of a research grant from Novartis.
The studies were funded by the National Cancer Institute, the National Human Genome Research Institute, the Melanoma Research Alliance, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Harvard Clinical and Translational Science Center NIH Training Grant Award, the National Institute of General Medical Sciences Grant, the Conquer Cancer Foundation, the Dana-Farber Leadership Council, the Starr Cancer Consortium, and the American Cancer Society.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
