Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé SCH772984, un inhibiteur d'ERK1/2, pour le traitement de tumeurs réfractaires aux inhibiteurs de BRAF et de MEK
The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the MAPK pathway. Selective BRAF and MEK inhibitors have shown clinical efficacy in melanoma patients. However, the majority of responses are transient and resistance is often associated with pathway reactivation of the ERK signaling pathway. Here we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 which displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency on tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.