Intrinsic Resistance to MEK Inhibition through BET Protein-Mediated Kinome Reprogramming in NF1-Deficient Ovarian Cancer.

ABSTRACT: Mutation or deletion of Neurofibromin 1 (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF-MEK-ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors (MEKi) were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of receptor tyrosine kinases (RTK) and their downstream RAF and PI3K signaling, thus overcomi

SUBMITTER: Kurimchak AM 

PROVIDER: S-EPMC6679760 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature