Resistance to BRAF inhibitors may be overcome with malaria drug

Though half of melanoma patients with the BRAF mutation respond positively to treatment with BRAF inhibitors, most develop resistance to the drugs and experience disease progression. A new study suggests a drug used to treat malaria may help to block the pathway that causes this BRAF inhibitor resistance.

A new preclinical study conducted by researchers with the University of Pennsylvania, Philadelphia, suggests that resistance may be due to an autophagy mechanism induced by the BRAF inhibitors vemurafenib and dabrafenib. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. The researchers found that blocking this pathway with the antimalarial drug hydroxychloroquine (HCQ) enables the BRAF inhibitors to perform more effectively.

According to lead author Ravi K. Amaravadi, M.D., co-leader of the Cancer Therapeutics Program at Penn Medicine’s Abramson Cancer Center, the study could lead to a combination therapy with BRAF inhibitors and autophagy inhibitors, which he says haven’t been thoroughly explored as a therapeutic option for patients with resistant tumors.

“Our laboratory studies using patient-derived melanoma samples identify autophagy as a new Achilles heel for BRAF mutant melanoma treated with BRAF inhibitors,” Dr. Amaravadi tells Dermatology Times. “While we are still at the very earliest stages of the clinical trials needed to test this idea, we hope that by blocking autophagy we can reverse resistance to these drugs and extend the lives of patients with advanced BRAF mutant melanoma.”

Dr. Amaravadi and his team have already begun a clinical trial for patients with advanced BRAF mutant melanoma to see how well tolerated HCQ is with the BRAF inhibitor vemurafenib. The results so far look promising, he reported in a news release.

Next steps include enrolling patients in the clinical trial investigating autophagy inhibitors in combination with BRAF inhibitors and potentially other, emerging new drug combinations proven to improve patient response.

The study was published online ahead of print in the Journal of Clinical Investigation.