TY - JOUR
T1 - mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer
AU - Kumari, Anju
AU - Gesumaria, Lisa
AU - Liu, Yan Jin
AU - Hughitt, V. Keith
AU - Zhang, Xiaohu
AU - Ceribelli, Michele
AU - Wilson, Kelli M.
AU - Klumpp-Thomas, Carleen
AU - Chen, Lu
AU - McKnight, Crystal
AU - Itkin, Zina
AU - Thomas, Craig J.
AU - Mock, Beverly A.
AU - Schrump, David S.
AU - Chen, Haobin
N1 - Publisher Copyright:
© 2023, Kumari et al.
PY - 2023/3/8
Y1 - 2023/3/8
N2 - Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. 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–AKT–mTOR 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.
AB - Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. 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–AKT–mTOR 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.
UR - http://www.scopus.com/inward/record.url?scp=85149557952&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.156657
DO - 10.1172/jci.insight.156657
M3 - Article
C2 - 36883564
AN - SCOPUS:85149557952
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 5
M1 - e156657
ER -