Combination of Gene Blockers May Cure Most Forms of Melanoma

While chemotherapy options exist for patients with melanoma resulting from a mutation in the BRAF gene, researchers have only recently described an approach to treat those with melanoma resulting from mutations of the NRAS gene.

The BRAF (v-Raf murine sarcoma viral oncogene homolog B1) gene encodes a protein known as serine/threonine-protein kinase B-Raf. Mutations in BRAF can cause disease by either congenital or acquired mutations. Acquired mutations in this gene have been found in several cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, and adenocarcinoma of the lung. About half of melanomas have a mutation in the BRAF gene, and inhibitors of BRAF such as Vemurafenib have been approved for the treatment of metastatic melanoma since August 2011.

About a fourth of melanomas are caused by mutations in the NRAS gene (neuroblastoma RAS viral oncogene homolog), but patients with this type of cancer have had no effective therapeutic options.

However, in a paper published in the September 16, 2012, online edition of the journal Nature Medicine, investigators at the University of Texas MD Anderson Cancer Center (Houston, USA) described using a new genetically engineered mouse model of NRAS-mutant melanoma to develop a potential therapy for this disease. In this model system the NRAS mutation could be induced to cause melanomas to form or inactivated to cause the melanomas to shrink. By analyzing the molecular basis for these effects, investigators were guided in the design of potential drugs that would do the same thing.

The investigators found that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activated apoptosis but not cell-cycle arrest in NRAS-mutant melanoma cells. However, when a MEK inhibitor was combined with an inhibitor of the major regulator of cell proliferation Cdk4 (cyclin-dependent kinase 4) a synergistic effect was produced that shrank tumors.

“The lack of a drug like the BRAF inhibitor that works against NRAS means that there is still no effective treatment option for NRAS-mutant patients to fall back on,” said senior author Dr. Lynda Chin, professor of genomic medicine at the University of Texas MD Anderson Cancer Center. “Developing an effective combination using existing drugs or drugs already in clinical development is a path to address this unmet need for this population of melanoma patients This new way of thinking about RAS signaling opens new opportunities to target other important signaling pathways in cancer, and the approach we have taken can now inform similar efforts to develop non-obvious combination strategies for other RAS mutated cancers.”

Related Links:
University of Texas MD Anderson Cancer Center