The pharmacological inhibition of the mitogen activated protein kinase (MAPK) pathway has shown significant activity in patients with mutant BRAF metastatic melanoma. Response rates to single agent BRAF and MEK inhibitors are approximately 50% and 25%, in patients with mutant BRAF metastatic melanoma. A higher response rate (76%) and prolonged tumor control is seen with the combination of the GSK BRAF inhibitor dabrafenib and MEK inhibitor trametinib, compared to single agent BRAF inhibitor alone.
Despite the dramatic clinical activity of combining BRAF and MEK inhibitors, only 41% of patients on combination therapy were progression-free at 1 year and there is currently limited information regarding mechanisms of resistance to this combination therapy.
We have systematically screened MAPK-inhibitor resistant melanoma tumours for mechanisms of resistance. Of 24 Australian melanoma patients treated initially with a BRAF inhibitor, 13 (54%) carry a known resistance driver, identified specifically in the progressing tumour. Of the three patients with multiple independently excised biopsies one patient had clear evidence of heterogeneity with each progressing-tumour carrying a different NRAS activating mutation and one patient had two independent resistance drivers within a single tumour.
Of five Australian melanoma patients treated initially with combination BRAF and MEK inhibitor, three were found to carry alterations affecting the MAPK cascade. The functional impact of these alterations will be discussed, and our strategy for defining novel resistance mechanisms outlined.