Vemurafenib resistance pathway yields targets for melanoma treatment
Researchers from Cancer Research UK have identified a family of proteins that mediate the development of resistance to vemurafenib, a BRAF enzyme inhibitor used to treat patients with advanced melanoma.
Writing in Nature Communications, the Manchester-based team says that mixed-lineage kinases (MLK1–4) are responsible for vemurafenib resistance, but that they may be amenable to therapeutic intervention.
“The good news is there are already experimental drugs that can block these enzymes in the laboratory,” lead author John Brognard, from the Cancer Research UK Manchester Institute, said in a statement. “And this research paves the way for the development of drugs to overcome vemurafenib resistance in melanoma patients.”
Vemurafenib is used to treat BRAF V600E-positive metastatic melanoma. Although vemurafenib is initially effective, resistance generally develops after around six months. In a series of in vitro studies, Brognard’s team showed that MLK1–4 enzymes directly phosphorylate MEK kinases to reactivate the MEK/ERK signalling pathway, independently of RAF kinases.
“This exciting research reveals that melanoma cells have enzymes acting like a manual override switch to regenerate growth signals — even after vemurafenib has switched them off,” Brognard explained.
The researchers also showed that increased expression of MLKs correlated with drug resistance in melanoma patients, and that MLK expression promoted resistance in a mouse model of melanoma and in V600E-positive cell lines.
Finally, the team characterised MLK1 mutations in a subset of patients with melanoma and found that several conferred enhanced activity toward the MEK/ERK pathway. Patients with these mutations may be predisposed to de novo resistance, and the data emphasise the importance of MLK1 in melanoma as a potential drug target, say the authors.
“Further studies will be aimed at determining whether [such] mutants of MLK1 can enhance melanomagenesis, suggesting MLK1 may be a melanoma oncogene,” they conclude.
Vemurafenib (Zelboraf) was made available in the UK in 2012.
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11138721
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