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BET protein degradation triggers DR5-mediated immunogenic cell death to suppress colorectal cancer and potentiate immune checkpoint blockade

Oncogene volume 40, pages 6566–6578 (2021)Cite this article

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Abstract

Bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers that play a critical role in oncogenesis by controlling the expression of oncogenes such as c-Myc. Targeting BET family proteins has recently emerged as a promising anticancer strategy. However, the molecular mechanisms by which cancer cells respond to BET inhibition are not well understood. In this study, we found that inducing the degradation of BET proteins by the proteolysis targeting chimeras (PROTAC) approach potently suppressed the growth of colorectal cancer (CRC) including patient-derived tumors. Mechanistically, BET degradation transcriptionally activates Death Receptor 5 (DR5) to trigger immunogenic cell death (ICD) in CRC cells. Enhanced DR5 induction further sensitizes CRC cells with a mutation in Speckle-type POZ protein (SPOP). Furthermore, DR5 is indispensable for a striking antitumor effect of combining BET degradation and anti-PD-1 antibody, which was well tolerated in mice and almost eradicated syngeneic tumors. Our results demonstrate that BET degradation triggers DR5-mediated ICD to potently suppress CRC and potentiate immune checkpoint blockade. These results provide a rationale, mechanistic insights, and potential biomarkers for developing a precision CRC therapy by inducing BET protein degradation.

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Fig. 1: BET degraders exhibited potent single-agent activity against colorectal cancer cells.
Fig. 2: The potent activity of BET degraders in colon cancer cells is mediated by ER stress- and DR5-dependent apoptosis.
Fig. 3: BETd260 suppresses in vivo tumor growth via DR5-mediated apoptosis.
Fig. 4: BETd260 suppresses CRC PDX tumors in an ER stress-dependent manner.
Fig. 5: BET degraders induce DR5-dependent immunogenic cell death.
Fig. 6: BETd260 combined with anti-PD-1 antibody potently suppresses CT26 tumors in a DR5-dependent manner.
Fig. 7: The BETd260/anti-PD-1 combination increases tumor infiltration of lymphocytes in a DR5-dependent manner in CT26 tumors.

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Acknowledgements

The authors thank our lab members for discussion and critical reading. This work was supported by the U.S. National Institutes of Health grants (R01CA203028, R01CA217141, R01CA236271, R01CA247231, and R01CA248112 to LZ; R01CA215758 to SW; U19AI068021 and R01CA215481 to JY; T32GM133332 to KE). This project used the Hillman Cancer Center Animal Facility, Cytometry Facility, and Tissue and Research Pathology Services, which are supported in part by P30CA047904.

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Authors and Affiliations

  1. UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA

    Jingshan Tong, Xiao Tan, Denise Risnik, Man Gao, Xiangping Song, Kaylee Ermine, Jian Yu & Lin Zhang

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Jingshan Tong, Xiao Tan, Denise Risnik, Xiangping Song, Kaylee Ermine & Lin Zhang

  3. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, P.R. China

    Xiao Tan & Liangfang Shen

  4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Man Gao & Jian Yu

  5. Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, P.R. China

    Xiangping Song

  6. Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA

    Shaomeng Wang

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  1. Jingshan Tong
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JT: experimental design, data acquisition, data analysis, manuscript writing; XT, DR, MG, XS: experimental methods, data acquisition; KE: manuscript editing; LS: data analysis; SW: key reagents, data analysis; JY: funding, supervision, manuscript editing; LZ: funding, supervision, experimental design, data analysis, manuscript writing.

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Correspondence to Lin Zhang.

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Tong, J., Tan, X., Risnik, D. et al. BET protein degradation triggers DR5-mediated immunogenic cell death to suppress colorectal cancer and potentiate immune checkpoint blockade. Oncogene 40, 6566–6578 (2021). https://doi.org/10.1038/s41388-021-02041-8

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