ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors
Menée sur des lignées cellulaires, cette étude identifie des mutations ponctuelles dans les gènes ERK1 et ERK2 en association avec la résistance à des inhibiteurs de la voie de signalisation MAPK
The use of targeted therapeutics directed against BRAFV600-mutant metastatic melanoma improves progression free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAFV600-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor-resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents.