Developing an Effective BET bromodomain inhibitor Drug Combo to Target SCLC

Division Of Basic Sciences - Nci

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Abstract

Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. BET inhibitors have shown promising preclinical activity in SCLC, but their broad sensitivity spectrum limits their clinical prospects. To identify therapeutics potentiating BET inhibitors, we performed high-throughput drug combination screens in SCLC cell lines. Inhibitors of the PI-3K-AKT-mTOR pathway were the top candidates from the screens. Among the therapeutics targeting this pathway, mTOR inhibitors showed the highest degree of synergy with BET inhibitors. Furthermore, the combination of mTOR and BET inhibitors showed superior antitumor efficacy and tolerability in vivo. Using both in vitro and in vivo SCLC models, we demonstrate that BET inhibitors activate the intrinsic apoptotic cascade, and mTOR inhibitors further enhance these apoptotic effects. Mechanistically, BET inhibitors activate the TSC2-mTOR-p70S6K1 signaling cascade by upregulating RSK3, an upstream kinase of TSC2. Activation of p70S6K1 leads to BAD phosphorylation and cell survival. mTOR inhibition blocks this survival signaling and potentiates the antitumor effects of BET inhibitors. Our results demonstrate that RSK3 upregulation is a novel resistance mechanism of BET inhibitors in SCLC, and mTOR inhibition overcomes this resistance and enhances apoptosis. These findings warrant further evaluation of the combination of mTOR and BET inhibitors in SCLC patients. Through independent low-throughput analysis, we confirmed the findings of the high-throughput analysis. One combination, mTOR inhibitor (mTORi) and BETi, showed superior anti-tumor efficacy in SCLC cell lines. Furthermore, the mTORi and BETi combination demonstrate superior tumor control and tolerability in several SCLC PDX models. Mechanistically, BETi induces apoptosis but its anti-tumor effect is counteracted by a concomitant transcriptome change that promotes cell survival. mTORi effectively blocks this survival cascade and enhances BETi-induced apoptosis in SCLC.