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Updated: May 21, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
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LRRK2 reduces the sensitivity to TKI and PD-1 blockade in ccRCC via activating LPCAT1

Yulong Hong1,2, Wei Li1,2, Zhuo Xing1,2

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

Oncogene
|March 23, 2025
PubMed

Insights

LRRK2 drives clear cell renal cell carcinoma (ccRCC) proliferation and reduces sensitivity to tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) therapies. Targeting LRRK2 with LR-protac enhances TKI and ICI treatment efficacy in ccRCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunotherapy

Background:

  • Combination therapy with tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) is a key strategy for advanced clear cell renal cell carcinoma (ccRCC).
  • Identifying novel druggable targets is crucial for enhancing the efficacy of current ccRCC treatments.

Purpose of the Study:

  • To identify new therapeutic targets for improving TKI and ICI combination therapy in ccRCC.
  • To investigate the role of Leucine-rich repeat kinase 2 (LRRK2) in ccRCC progression and its impact on treatment sensitivity.

Main Methods:

  • Analysis of public ccRCC datasets and protein kinase inhibitor data to identify potential targets.
  • Investigating the mechanism of LRRK2 in ccRCC cell proliferation and its interaction with lipid metabolism modulator LPCAT1.
  • Developing and testing an LR-protac molecule to target kinase-independent LRRK2 activity.

Main Results:

  • LRRK2 was identified as a target upregulated by HIF2A, driving ccRCC proliferation independently of its kinase activity.
  • LRRK2 was found to inhibit LPCAT1 degradation, reducing sensitivity to TKI and PD-1 blockade by upregulating IL-1β.
  • The developed LR-protac effectively decreased LRRK2 levels and potentiated the antitumor effects of TKI and PD-1 blockade in ccRCC models.

Conclusions:

  • LRRK2 is a critical mediator of ccRCC proliferation and resistance to TKI and ICI therapies.
  • Targeting the kinase-independent function of LRRK2 via LR-protac represents a promising strategy to improve ccRCC treatment outcomes.

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