mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer

Abstract

PurposeSCLC 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 in this malignancy. Drug combination could be a solution.Experimental designWe performed high-throughput drug combination screens in SCLC cell lines to identify potential therapeutics synergizing with BET inhibitors. Validation was performed in SCLC cell lines and patient-derived xenograft models. Genome-wide RNA sequencing of xenograft tumors was performed to determine the mechanism underlying the synergy of the drug combination.ResultsInhibitors 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 in vitro. Furthermore, the combination of these two classes of drugs 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 cascade and potentiates the antitumor effects of BET inhibitors.ConclusionsOur results demonstrate that RSK3 upregulation is a novel resistance mechanism of BET inhibitors in SCLC, and mTOR inhibition can overcome this resistance and enhance apoptosis. These findings provide a rationale to evaluate the combination of mTOR and BET inhibitors in patients with SCLC.

Somatic gain-of-function mutations in BUD13 promote oncogenesis by disrupting Fbw7 function

“…We next tried to find a potential therapeutic direction to treat colon cancer cells expressing these cancerous RSK3 phosphorylation deficient mutations. To this end, we found that either RSK3 mediates mTOR inhibition resistance in breast cancer ( Serra et al, 2013 ) or mTOR contributes to RSK3 inhibition in small-cell lung cancer ( Kumari et al, 2021 Preprint ). Thus, we examined effects of mTOR inhibitors in regulating growth of DLD1 cells expressing WT-, R156C-, or R230Q-BUD13.…”

BET Inhibitors Target the SCLC-N subtype Small Cell Lung Cancer by Blocking NEUROD1 Transactivation

“…One potential solution to this obstacle is to use drug combinations that would be effective against two or more subtypes. For instance, in another study, we have found that mTOR inhibitors could potentiate the antitumor activities of BETi and make the latter drug effective in the BETi-resistant SCLC lines (30).…”