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Intrinsic Resistance to MEK Inhibition Through BET Protein Mediated Kinome Reprogramming in NF1-deficient Ovarian Cancer
Mol Cancer Res. 2019 May 1;17(8) :1721-1734
PMID: 31043489 PMCID: PMC6679760 URL: https://www.ncbi.nlm.nih.gov/pubmed/31043489
AbstractMutation 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 (RTKs) and their downstream RAF and PI3K signaling, thus 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 that BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC. Implications: Our findings suggest MEK inhibitors will likely not be effective as single agent therapies in NF1-deficient EOC due to kinome reprogramming. Co-targeting BET proteins in combination with MEK inhibitors to block reprogramming at the transcriptional level may provide an epigenetic strategy to overcome MEK inhibitor resistance in NF1-deficient EOC.
Notes1557-3125 Kurimchak, Alison M Shelton, Claude Herrera-Montavez, Carlos Duncan, Kelly E Chernoff, Jonathan Duncan, James S Journal Article United States P30 CA006927/CA/NCI NIH HHS/ Mol Cancer Res. 2019 May 1. pii: 1541-7786.MCR-18-1332. doi: 10.1158/1541-7786.MCR-18-1332.