mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.
mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.
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DOI：
10.1172/jci.insight.156657
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发表时间：
2023-03-08
期刊：
影响因子：
8
通讯作者：
Chen, Haobin
中科院分区：
文献类型：
--
作者：
Kumari, Anju;Gesumaria, Lisa;Liu, Yan-Jin;Hughitt, V. Keith;Zhang, Xiaohu;Ceribelli, Michele;Wilson, Kelli M.;Klumpp-Thomas, Carleen;Chen, Lu;McKnight, Crystal;Itkin, Zina;Thomas, Craig J.;Mock, Beverly A.;Schrump, David S.;Chen, Haobin
小细胞肺癌（SCLC）是一种难治性恶性肿瘤，治疗选择有限。溴结构域和末端外结构域抑制剂（BETis）在小细胞肺癌中显示出有希望的临床前活性，但广泛的敏感谱限制了它们的临床前景。在这里，我们进行了无偏倚的高通量药物组合筛选，以确定可以增强BETis在SCLC中的抗肿瘤活性的治疗方法。我们发现靶向PI-3 K-AKT-mTOR通路的多种药物与BETis协同作用，其中mTOR抑制剂（mTORIS）显示出最高的协同作用。使用源自SCLC患者的异种移植物模型的各种分子亚型，我们证实mTOR抑制增强了BET的体内抗肿瘤活性，而基本上不增加毒性。此外，在体外和体内SCLC模型中，BET诱导细胞凋亡，并且这种抗肿瘤作用通过组合mTOR抑制而进一步放大。在机制上，BET通过激活内在凋亡途径诱导SCLC中的凋亡。然而，BET抑制导致RSK 3上调，其通过激活TSC 2-mTOR-p70 S6 K1-BAD级联来促进存活。mTORis阻断这种保护性信号传导并增加BET抑制诱导的细胞凋亡。我们的研究结果揭示了RSK 3诱导在BET抑制后的肿瘤存活中的关键作用，并保证了在SCLC患者中进一步评估mTORis和BET is的组合。
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.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8
作者：
Bolin, Sara;Borgenvik, Anna;Swartling, Fredrik J.
通讯作者：
Swartling, Fredrik J.
影响因子：
11.2
作者：
Hann, Christine L.;Daniel, Vincent C.;Rudin, Charles M.
通讯作者：
Rudin, Charles M.