Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy

Unsustained enzyme inhibition is a barrier to targeted therapy for cancer. Here, resistance to a class I PI3K inhibitor in a model of metastatic breast cancer driven by PI3K and MYC was associated with feedback activation of tyrosine kinase receptors (RTKs), AKT, mTOR, and MYC. Inhibitors of bromodomain and extra terminal domain (BET) proteins also failed to affect tumor growth. Interestingly, BET inhibitors lowered PI3K signaling and dissociated BRD4 from chromatin at regulatory regions of insulin receptor and EGFR family RTKs to reduce their expression. Combined PI3K and BET inhibition induced cell death, tumor regression, and clamped inhibition of PI3K signaling in a broad range of tumor cell lines to provide a strategy to overcome resistance to kinase inhibitor therapy. [Display omitted] •BET inhibitors lower the expression of RTKs and the PI3K signal•BET inhibition blocks BRD4 binding at the promoter of several RTKs•Activation of AKT, mTOR, and MYC due to PI3K inhibition is blocked by BET inhibitors•Targeting BRD4 and PI3K together, but not alone, inhibits growth of many tumor cells Inhibition of PI3K induces feedback activation of upstream RTKs and quick rebound of the pathway activity. Stratikopoulos et al. show that BRD4 is important for the feedback activation of many RTKs and that combined PI3K and BET inhibition sustains PI3K pathway inhibition and enhances tumor cell killing.