Combating drug resistance in melanoma

Resistance to a treatment for advanced melanoma could be prevented by blocking a druggable family of proteins. Cancer Research UK scientists at the CRUK Manchester Institute have found that the mixed-lineage kinases (MLK) family of four enzymes undoes the tumour-shrinking effect of vemurafenib, a treatment for the deadly form of cancer. Approximately half of metastatic melanomas are caused by a fault in BRAF, a cell growth gene, which causes signal telling cells to multiply. Vemurafenib blocks BRAF and stops the growth of cancerous cells, but the cells usually find a different way of switching the pathway back on. Most metastatic melanoma patients stop responding to the drug within six months, leading to relapse. The new research found that MLK enzymes can be responsible for reactivating the BRAF pathway, even in the presence of vemurafenib; by blocking these enzymes they hope to stop resistance so the cancer cells are still vulnerable to the drug. The findings – published in Nature Communications­ – also found some patients had additional gene mutations that switched on the MLK genes on, meaning they became resistant more quickly. “This exciting research reveal that melanoma cells have enzymes acting like a manual override switch to generate growth signals – even after vemurafenib has switched them off,” said lead author Dr John Brognard. “Additionally, this family of enzymes are turned on in metastatic melanomas that are not caused by BRAF, suggesting they may serve as a new target in metastatic melanomas for which there are limited treatments options.” Brognard said the good news is that experimental drugs to block MLK enzymes are already in the laboratory, and that this research is paving the way for development of drugs to overcome vemurafenib resistance in melanoma patients. “This exciting research opens new routes to treat this disease,” said Professor Nic Jones, Cancer research UK’s chief scientist and director of the Manchester Cancer Research Centre. “Thanks to people’s generosity we’ve funded research that revealed that the BRAF gene is behind around half of all menalomas. And several drugs that target BRAF are now showing promise in clinical trials.” Mixed-lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors