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LRRK2 reduces the sensitivity to TKI and PD-1 blockade in ccRCC via activating LPCAT1

Oncogene volume 44, pages 1761–1776 (2025)Cite this article

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Abstract

Tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) combination therapy is emerging as a major therapeutic strategy for advanced clear cell renal cell carcinoma (ccRCC). To define the druggable targets for improvement of TKI and ICI combination therapy in ccRCC, we analyzed a commercial protein kinase inhibitor dataset and a public ccRCC dataset and identified LRRK2 as a potential candidate that can be targeted by a small molecule inhibitor. We demonstrated that LRRK2 was transcriptionally upregulated by HIF2A and enabled to drive proliferation of ccRCC cells in a manner independent of its kinase activity. LRRK2 inhibits the RBX1-mediated degradation of lipid metabolism modulator LPCAT1 to reducing the sensitivity to TKI and PD-1 blockade in ccRCC. Specifically, LRRK2/LPCAT1 upregulated IL-1β expression levels through AKT and also increased IL-1β shearing by activating inflammasome. To target the kinase-independent activity of LRRK2, we developed an LR-protac and showed that LR-protac decreased LRRK2 protein level and enhanced the antitumor effect of PD-1 blockade and TKI in ccRCC. These data indicate that LRRK2 is a viable target for improvement of the efficacy of PD-1 blockade and TKI in ccRCC.

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Fig. 1: LRRK2 is transcriptionally upregulated by HIF2A and enhances ccRCC proliferation in a kinase-independent manner.
Fig. 2: LRRK2 disrupts lipid metabolism in ccRCC.
Fig. 3: LRRK2 promotes the proliferation of ccRCC cells by activating lipid metabolism associated with the LPCAT1-AKT signaling pathway.
Fig. 4: LRRK2 protects LPCAT1 from degradation mediated by RBX1 in ccRCC.
Fig. 5: LRRK2 upregulates the IL-1β though LPCAT1 in ccRCC cells.
Fig. 6: LRRK2 decreases the sensitivity of ccRCC to ICIs and TKIs.
Fig. 7: LR-protac degrades LRRK2 to increase the sensitivity of ccRCC to PD-1 blockade and TKIs.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request. The data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE264320.

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Acknowledgements

We would like to thank Shanghai BioProfile Biotechnology (Shanghai, China) for technical support. We would like to thank ProMab Biotechnologies, Inc. (Changsha, China) for their antibody.

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Author notes

  1. These authors contributed equally: Yulong Hong, Wei Li, Zhuo Xing.

Authors and Affiliations

  1. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Yulong Hong, Wei Li, Zhuo Xing, Liang Zhu, Wei Xiong & Wentao Liu

  2. Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Disease, Changsha, 410011, China

    Yulong Hong, Wei Li, Zhuo Xing, Liang Zhu, Wei Xiong & Wentao Liu

  3. Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Minghao Lu & Tianyu Tang

  4. Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Minghao Lu & Tianyu Tang

  5. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Huan Zhang

  6. Robotic Minimally Invasive Surgery Center, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Shangqing Ren

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  1. Yulong Hong
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Contributions

Yulong Hong: Methodology; Wei Li: Methodology; Zhuo Xing: Methodology; Minghao Lu: Methodology; Tianyu Tang: Formal analysis; Liang Zhu: Formal analysis; Wei Xiong: Formal analysis; Wentao Liu: Project administration, Investigation; Huan Zhang: Investigation; Shangqing Ren: Project administration, Investigation.

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Correspondence to Huan Zhang, Wentao Liu or Shangqing Ren.

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We confirm that all methods are performed in accordance with the relevant guidelines and regulations. The study was approved by the Animal Use and Care Committees at the Second Xiangya hospital, Central South University (License No. 20240511). We obtained informed consent from all patients to whom the specimens belonged. We obtained informed consent from all patients for the use of their specimens.

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Hong, Y., Li, W., Xing, Z. et al. LRRK2 reduces the sensitivity to TKI and PD-1 blockade in ccRCC via activating LPCAT1. Oncogene 44, 1761–1776 (2025). https://doi.org/10.1038/s41388-025-03289-0

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