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 1

Clinical BETi promote BCL6 expression.

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Clinical BETi promote BCL6 expression. (A) BCL6 expression in KRAS-mutan...
(A) BCL6 expression in KRAS-mutant NSCLC cells in response to clinical drug treatments. Cells were treated with the indicated drugs at a concentration of their one-half IC50s for 48 hours. Graph shows the relative BCL6 protein levels, normalized to GAPDH. **P < 0.01, by unpaired, 2-tailed Student’s t test, comparing the relative BCL6 protein level of the OTX015-treated group with that of the vehicle-treated group. (B and C) OTX015 upregulated BCL6 expression at the (B) protein and (C) transcription levels in a time-dependent manner. A549, H292, and H441 cells were treated with OTX015 for the indicated durations. BCL6 expression was detected by Western blotting and PCR assays. (D) BCL6 protein levels in cells upon treatment with BETi (OTX015, JQ1, I-BET762, and AZD5153) or a BRD9i (BI7273). (E) BETi upregulated BCL6 expression in a set of KRAS-mutant NSCLC cells. Cells were treated with OTX015 (300 nM), JQ1 (300 nM), or DMSO for 6 hours. Cell lysates were probed with antibodies against BCL6 and GAPDH. (F) OTX015 upregulated BCL6 levels in 2 primary NSCLC cell lines harboring a KRASG12C mutation. Left: DNA-Seq of exon 2 in the KRAS gene. Right: BCL6 levels in LC087A05 and LC308B01 cells exposed to OTX015 (300 nM) or DMSO for 6 hours. (G) BCL6 protein levels in orthotopic xenografts. During the 1-week treatment with OTX015, tumor tissue was isolated on day 2 and day 7, followed by immunoblot analysis for BCL6 expression. Three biologically independent samples per group are shown.