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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月22日

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  • Yulong Hong,
  • Wei Li,
  • Zhuo Xing,
  • Minghao Lu,
  • Tianyu Tang,
  • Liang Zhu,
  • Wei Xiong,
  • Huan Zhang,
  • Wentao Liu,
  • Shangqing Ren

摘要

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.