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Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment the antitumor activities of BETis in SCLC. We found that multiple drugs targeting the PI-3K\u2013AKT\u2013mTOR pathway synergize with BETis, among which mTOR inhibitors (mTORis) show the highest synergy. Using various molecular subtypes of the xenograft models derived from patients with SCLC, we confirmed that mTOR inhibition potentiates the antitumor activities of BETis in vivo without substantially increasing toxicity. Furthermore, BETis induce apoptosis in both in vitro and in vivo SCLC models, and this antitumor effect is further amplified by combining mTOR inhibition. Mechanistically, BETis induce apoptosis in SCLC by activating the intrinsic apoptotic pathway. However, BET inhibition leads to RSK3 upregulation, which promotes survival by activating the TSC2-mTOR-p70S6K1-BAD cascade. mTORis block this protective signaling and augment the apoptosis induced by BET inhibition. Our findings reveal a critical role of RSK3 induction in tumor survival upon BET inhibition and warrant further evaluation of the combination of mTORis and BETis in patients with SCLC.<\/jats:p>","DOI":"10.1172\/jci.insight.156657","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T14:01:14Z","timestamp":1678197674000},"source":"Crossref","is-referenced-by-count":19,"title":["mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5130-4774","authenticated-orcid":true,"given":"Anju","family":"Kumari","sequence":"first","affiliation":[{"name":"Thoracic Surgery Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9600-8757","authenticated-orcid":true,"given":"Lisa","family":"Gesumaria","sequence":"additional","affiliation":[{"name":"Thoracic Surgery Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8090-8999","authenticated-orcid":true,"given":"Yan-Jin","family":"Liu","sequence":"additional","affiliation":[{"name":"Thoracic Surgery Branch and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0787-9559","authenticated-orcid":true,"given":"V. 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