BCL6 confers KRAS-mutant non–small-cell lung cancer resistance to BET inhibitors
Jiawei Guo, … , Mingyao Liu, Xiufeng Pang
Jiawei Guo, … , Mingyao Liu, Xiufeng Pang
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e133090. https://doi.org/10.1172/JCI133090.
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Research Article Oncology

BCL6 confers KRAS-mutant non–small-cell lung cancer resistance to BET inhibitors

Abstract

The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors; however, inherent resistance remains a major challenge in the clinic. Recently, the emerging role of the oncoprotein B cell lymphoma 6 (BCL6) in tumorigenesis and stress response has been unveiled. Here, we demonstrate that BCL6 was upregulated upon BET inhibition in KRAS-mutant cancers, including non–small-cell lung cancer (NSCLC). We further found that BRD3, not BRD2 or BRD4, directly interacted with BCL6 and maintained the negative autoregulatory circuit of BCL6. Disrupting this negative autoregulation by BET inhibitors (BETi) resulted in a striking increase in BCL6 transcription, which further activated the mTOR signaling pathway through repression of the tumor suppressor death-associated protein kinase 2. Importantly, pharmacological inhibition of either BCL6 or mTOR improved the tumor response and enhanced the sensitivity of KRAS-mutant NSCLC to BETi in both in vitro and in vivo settings. Overall, our findings identify a mechanism of BRD3-mediated BCL6 autoregulation and further develop an effective combinatorial strategy to circumvent BETi resistance in KRAS-driven NSCLC.

Authors

Jiawei Guo, Yanan Liu, Jing Lv, Bin Zou, Zhi Chen, Kun Li, Juanjuan Feng, Zhenyu Cai, Lai Wei, Mingyao Liu, Xiufeng Pang

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Figure 7

mTOR inhibition sensitizes KRAS-mutant NSCLC to BETi.

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mTOR inhibition sensitizes KRAS-mutant NSCLC to BETi. (A) DAPK2 overexpr...
(A) DAPK2 overexpression suppressed mTOR and S6K phosphorylation. H441 cells infected with a pCDH-DAPK2 or pCDH control virus were subjected to immunoblot analysis. Immunoblots were contemporaneous and run in parallel from the same biological replicate, respectively. (B) Colony formation of H441 and A549 cells with DAPK2 overexpression. Results are representative of 3 independent experiments. Data represent the mean ± SEM of biological triplicates. ***P < 0.001, by unpaired, 2-tailed Student’s t test, comparing the DAPK2OE group with the vector group in the presence of OTX015. (C) Synergistic interaction between BETi (OTX015 and JQ1) and mTORi (rapamycin and ridaforolimus) in KRAS-mutant NSCLC cells. A549 and H441 cells were treated for 48 hours with various concentrations of the indicated inhibitors. The concentrations of BETi or mTORi were used in a 2-fold dilution series (0.78, 1.56, 3.13, 6.25, 12.5, and 25 μM for individual BETi; 0.78, 1.56, 3.13, 6.25, 12.5, and 25 nM for individual mTORi). Relative cell viability was subsequently measured. Data represent the mean ± SD of biological triplicates. CI values at each concentration were calculated using CalcuSyn software. (D) Tumor growth curves of LACPDX (n = 8 per group). The mean AUC of tumor volumes on day 23 is shown. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA. (E) Tumor weights at the end of therapy. Each dot represents a tumor from an individual mouse. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA.