Overcoming Melanoma Drug Resistance

The MAPK signaling pathway regulates cell proliferation by transmitting chemical signals from outside of cells to their nuclei. Ten percent of all human cancers and half of all metastatic melanomas result from mutations in BRAF, a gene that codes for a protein in the MAPK pathway. By far the most common melanoma BRAF mutation is BRAFV600E—a single-nucleotide mutation that causes glutamic acid to substitute for valine in the BRAF protein.

The U.S. Food and Drug Administration has approved several BRAF-inhibiting drugs for treating tumors possessing the BRAFV600E mutation. Unfortunately, nearly all tumors eventually develop resistance to the drugs. A principal reason is reactivation of the MAPK pathway, which induces BRAF to form drug-resistant dimers (two BRAF molecules associated together).

A study published online on September 1 in Nature Communications by Evripidis Gavathiotis, Ph.D., and colleagues describes a drug that shows promise for inhibiting BRAF dimers. The researchers designed a BRAF dimer inhibitor based on the molecular structure of a drug called Ponatinib, approved by the FDA for treating chronic myelogenous leukemia. Since BRAF dimers encourage melanoma tumors to develop drug resistance, the new drug may help extend the lives of melanoma patients.

Dr. Gavathiotis is professor of biochemistry and of medicine at Einstein. Bogos Agianian, Ph.D., co-first author and co-corresponding author, is research assistant professor of biochemistry at Einstein. Xiomaris Cotto-Rios, Ph.D., is co-first author and former American Cancer Society postdoctoral fellow in the Gavathiotis laboratory.