GSE127886
Intrinsic Resistance to MEK Inhibition Through BET Protein Mediated Kinome
Mutation or deletion of Neurofibromin (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 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 RTKs and their downstream RAF and PI3K signaling overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of BET proteins using BET bromodomain inhibitors (BETi) blocked MEKi-induced RTK reprogramming, indicating BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC. Overall design: Examination of the global effects on transcription in response to trametinib (GSK212) in A1847 cells.