Abstract
1 Department of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia, 2 Department of Pathology, University of Melbourne, Parkville, VIC, Australia, 3 Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia, 4 Sir Peter MacCallum Department of Oncology, University of Melbourne, East Melbourne, VIC, Australia, 5 Molecular Oncology Laboratory, Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia, 6 Translational Research Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
Highlights
The Combination of BRAF and MEK Inhibition in Advanced MelanomaThe discovery and development of small molecule inhibitors of mutant BRAF kinase and MEK kinase have revolutionized the care of patients with melanoma
Specialty section: This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology
When used as single agents, the BRAF inhibitors, vemurafenib and dabrafenib, improve progression free and overall survival when compared to chemotherapy with dacarbazine [1, 2]
Summary
The discovery and development of small molecule inhibitors of mutant BRAF kinase and MEK kinase have revolutionized the care of patients with melanoma. Interesting combination therapy substantially improved the complete response rate from 4–9 to 10–13% across the three studies In each of these three trials, it was clear that combination therapy reduced the frequency of cutaneous side effects that have been attributed to BRAF inhibitor-induced “paradoxical activation” of RAF kinases in cells without BRAF mutations. This exactly predicts the findings from preclinical studies where MEK inhibition downstream of activated RAF kinases reduces signaling through ERK and the outputs of paradoxical activation [10]. This is probably due to paradoxical activation of RAF kinases reducing the effects of MEK inhibition, and MEK inhibition reducing the effects of paradoxical activation of RAF kinases
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