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mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer
Anju Kumari, … , David S. Schrump, Haobin Chen
Anju Kumari, … , David S. Schrump, Haobin Chen
Published March 8, 2023
Citation Information: JCI Insight. 2023;8(5):e156657. https://doi.org/10.1172/jci.insight.156657.
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Research Article Oncology

mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer

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Abstract

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.

Authors

Anju Kumari, Lisa Gesumaria, Yan-Jin Liu, V. Keith Hughitt, Xiaohu Zhang, Michele Ceribelli, Kelli M. Wilson, Carleen Klumpp-Thomas, Lu Chen, Crystal McKnight, Zina Itkin, Craig J. Thomas, Beverly A. Mock, David S. Schrump, Haobin Chen

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Figure 3

mTOR inhibition augments the antitumor effects of BETis by increasing apoptosis in vivo.

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mTOR inhibition augments the antitumor effects of BETis by increasing ap...
(A and B) The combination of everolimus (3 mg/kg, daily) and NHWD870 (3 mg/kg, daily) was more effective than single agents in controlling tumor growth as shown in A and prolonging survival as shown in B in LX33, an SCLC-N PDX model (n ≥ 10 per group). (C) Relative BW changes of the mice in A. (D and E). The combination of everolimus and AZD5153 (both at 1 mg/kg, daily) was more effective than single agents in controlling tumor growth as shown in D and prolonging survival as shown in E in LX95, an SCLC-A PDX model (n = 9 per group). (F) Relative BW changes of the mice in D. (G and H) Representative images and quantification of cleaved caspase 3 IHC staining in LX95 PDX tumors after a 1-week treatment of everolimus (2 mg/kg, daily), NHWD870 (1.5 mg/kg, daily), or the combination (everolimus 1.5 mg/kg and NHWD870 1 mg/kg, daily). n = 7 per group. Horizontal lines in H represent medians. The significance of the 2-group comparisons was determined using the Student’s t test with the FDR multiple comparison corrections in A and D, the log-rank test in B and E, and the ANOVA test with Dunnett’s multiple test corrections in H. Statistically significant differences in tumor volumes between the BETi single-agent and vehicle groups are indicated with black asterisks, while red asterisks mark the statistically significant changes between the combo and the BETi single-agent groups in A and D. Dotted lines represent 10% weight gain or loss in C and F. Data are shown as mean ± SD; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. A, AZD5153; E, everolimus; N, NHWD870; V, vehicle; CC3, cleaved caspase 3. Scale bar: 20 µm.

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