Researchers identify a new target for treating drug-resistant melanoma.[dnberty/iStock]
Researchers identify a new target for treating drug-resistant melanoma.[dnberty/iStock]

By now, it has become readily apparent to most that protracted exposure to the sun and UV rays leads to increased incidences of skin cancer, with melanoma leading the way as the most deadly form. What has had scientists perplexed in recent years is not the cause of melanoma, but the mechanisms underlying the switch to a drug-resistance phenotype toward a group of commonly prescribed drugs called BRAF inhibitors.

Now, investigators at the Sanford-Burnham Medical Researcher Institute believe they have charted the molecular pathways that lead to melanoma resistance and have developed methods to overcome the resistance phenotype—possibly providing a novel effective approach for improving the clinical outcome of patients with BRAF inhibitor resistant tumors.  

Typically, BRAF inhibitors have been prescribed for late-stage melanoma cases and represent a significant advance in the clinical management of the disease, relative to previous first-line therapies. Moreover, since roughly 50% of melanoma tumors are drive by mutations in the BRAF gene, this class of drug seems a logical choice for therapeutic intervention. However, although BRAF inhibitors rapidly and effectively shrink melanoma tumors, success is often limited as most tumors become resistant to the drugs within a few months.    

“Melanoma tumors can develop resistance to BRAF inhibitors by using alternate signaling pathways that promote cell growth,” explained Ze'ev Ronai, Ph.D., scientific director of Sanford-Burnham's La Jolla campus and senior author on the current study. “Our study has identified a different pathway, JAK1, as a driver of resistance to BRAF inhibitors, and suggests that targeting JAK1 could overcome such resistance, thereby improving the durability of the response to BRAF inhibitors.”

The findings from this study were published recently in Cell Reports through an article entitled “Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation.”

The investigators analyzed drug-resistance within human tumor biopsies, mice transfected with human melanoma tumors, and in vitro melanoma cell lines. What the researchers found was that resistant tumors had increased levels of the tyrosine kinase signaling molecule, JAK1, which led to increased expression of epidermal growth factor (EGFR)—a receptor tyrosine kinase that has been shown to promote cell proliferation.

Consequently, the Sanford-Burnham scientists discovered that the increase in JAK1 was due to low levels of the protein that regulates its expression, ubiquitin ligase RNF125.

With all of this information in tow, the researchers sought to determine if the drug resistance phenotype could be circumvented. They identified that, not only does RNF125 expression in melanoma specimens inversely correlate with BRAF inhibitor resistance, but the combination of JAK, BRAF, and EGFR inhibitors was able to overcome the drug-resistance phenotype.

“By helping us understand that lower levels of RNF125 confer resistance to BRAF inhibitors, we have a new strategy to stratify patients for currently approved therapy versus participation for human clinical trials to investigate whether targeting JAK1 will be more effective in patients whose tumors exhibit reduced RNF125,” concluded co-author Keith Flaherty, M.D., associate professor at Harvard Medical School and director of Developmental Therapeutics Cancer Center, Massachusetts General Hospital. “It will be important to determine whether JAK1 therapy alone or in combination with EGFR and BRAF inhibitors will elicit a better response.”