Supplementary Data from CDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer

Li, Wei; Guo, Feng; Zeng, Ruijiang; Liang, Huaiyuan; Wang, Yinhuai; Xiong, Wei; Wu, Heshui; Yang, Chunguang; Jin, Xin

doi:10.1158/0008-5472.26711002.v1

Supplementary Data from CDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer

https://doi.org/10.1158/0008-5472.26711002

journal contribution

posted on 2024-08-15, 07:29 authored by Wei Li, Feng Guo, Ruijiang Zeng, Huaiyuan Liang, Yinhuai Wang, Wei Xiong, Heshui Wu, Chunguang Yang, Xin Jin

<p>Supplementary information</p>

Funding

National Natural Science Foundation of China (NSFC)

Science Fund for Distinguished Young Scholars of Hunan Province (湖南省杰出青年自然科学基金)

Key Project of Research and Development Plan of Hunan Province

Key Research and Development Program of Hunan Province of China (湖南省重点研发计划)

Innovation-Driven Project of Central South University

Health and Family Planning Commission of Hunan Province (湖南卫生和计划生育委员会)

History

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DOI - Is supplement to CDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer

ARTICLE ABSTRACT

The efficacy of immunotherapy in patients with prostate cancer is limited due to the “cold” tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis is involved in innate immunity and has been increasingly recognized as a candidate target for cancer immunotherapy. Here, we found that treatment with CDK4/6 inhibitors stimulates the STING pathway and enhances the antitumor effect of STING agonists in prostate cancer. Mechanistically, CDK4/6 phosphorylated TBK1 at S527 to inactivate the STING signaling pathway independent of RB1 in prostate cancer cells. CDK4/6-mediated phosphorylation of RB1 at S249/T252 also induced the interaction of RB1 with TBK1 to diminish the phosphorylation of TBK1 at S172, which suppressed STING pathway activation. Overall, this study showed that CDK4/6 suppresses the STING pathway through RB1-dependent and RB1-independent pathways, indicating that CDK4/6 inhibition could be a potential strategy to overcome immunosuppression in prostate cancer.Significance: Inhibiting CDK4/6 activates STING-TBK1-IRF3 signaling in prostate cancer by regulating TBK1 phosphorylation, suggesting that the combination of CDK4/6 inhibitors and STING agonists could be an effective approach to stimulate innate immunity.