Cutaneous melanoma ranks among the fastest rising human malignancies in annual incidence and is highly lethal when detected at advanced stages. Standard chemotherapy often targets fast dividing cells, in both the tumor as well as some normal tissues of the patient, giving rise to unwanted side effects. Targeting a specific feature of cancer not present in the normal cells would reduce undesirable side effects. A small molecule (PLX4032) targeting a common melanoma mutation, V600EB-RAF, is showing unprecedented promise in advanced stages of clinical trials (80 percent of patients respond if their tumors harbor the V600EB-RAF mutation) but drug resistance occurs over time and leads to clinical relapse. Lo reported in Nature the discovery of two means by which melanomas escape from PLX4032, which suggest new treatment strategies that are testable in clinical trials. Discovering mechanisms of acquired PLX4032 resistance is logically the first step in constructing a therapeutic strategy closer to a cure. Lo will study tissues derived from clinical trial patients. He will enlarge this tissue collection by collaborating among distinct clinical trial sites. Finally, because finding a specific mechanism among the myriad of cancer-related changes is akin to finding a needle in a haystack, he should capitalize on the latest, “high-throughput” genomic technologies. By harnessing the speed of “next-generation” DNA sequencing technology, he will examine the protein-coding regions of the melanoma genomes for key genetic alterations that account for acquired resistance. This effort will inform clinical trials and will help guide patient care.
Roger S. Lo, M.D., Ph.D., is assistant professor in the division of dermatology/department of medicine and the department of molecular and medical pharmacology at the David Geffen School of Medicine at the University of California.
Updated: April 4, 2011