medwireNews: Findings from a study carried out in mice suggest that an intermittent dosing strategy may be the answer to combating lethal tumor resistance to the BRAF inhibitor vemurafenib, in patients with late-stage BRAF-mutated melanoma.
The investigating team, led by Martin McMahon (University of California San Francisco, USA) and Darrin Stuart (Novartis Institutes for Biomedical Research, Emeryville, California, USA), reports that in a mouse model, vemurafenib-resistant melanomas appear to become dependent on a constant supply of the drug to proliferate. Therefore, when treatment is halted, the tumors begin to shrink.
The researchers also tested a discontinuous dosing strategy in the mice and found that it seemed to be effective at preventing the onset of lethal drug-resistant disease.
"Remarkably, intermittent dosing with vemurafenib prolonged the lives of mice with drug-resistant melanoma tumors," said McMahon in a press statement, adding that it is possible that such an approach may have a similar effect in humans with advanced drug-resistant melanoma.
Over half of all human melanomas have mutations in the BRAF (V600E) oncoprotein, making them susceptible to treatment with vemurafenib. However, many patients relapse with deadly drug-resistant disease following a good initial response to treatment.
The investigators found that increased production of the BRAF protein by the mouse tumors was responsible for their drug-resistant state. They showed that partial suppression of BRAF to levels seen in parental non-resistant melanoma cells, which could be achieved by a period of drug withdrawal, resensitized the tumors to vemurafenib.
Mice with vemurafenib-resistant tumors were either treated continuously or on a 4 weeks on/2 weeks off dosing schedule with vemurafenib 15 mg/kg twice daily. Writing in Nature, the researchers report that mice treated continuously with vemurafenib all died within 100 days, whereas all the mice in the intermittent group were still alive and free of drug-resistant disease at 200 days.
"Vemurafenib has revolutionized treatment of a specific subset of melanoma expressing mutated BRAF, but its long-term effectiveness is diminished by the development of drug resistance," said McMahon in the press statement.
"By seeking to understand the mechanisms of drug resistance, we have also found a way to enhance the durability of the drug response via intermittent dosing."