Evidence map›Paper›PMID 40121376›Full record

ArticleOncogene2025

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

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

Abstract read
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In one paragraph

Article in Oncogene, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Article
  2. Review
  3. Review
  4. Review
  5. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Yulong Hong *Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Wei Li *Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Zhuo Xing *Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Minghao LuDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Tianyu TangDepartment of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Liang ZhuDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Wei XiongDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Huan ZhangDepartment of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. drzhanghuan@hust.edu.cn.
Wentao LiuDepartment of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China. xyeyylwt@csu.edu.cn.ORCID http://orcid.org/0000-0002-2123-3247
Shangqing RenRobotic Minimally Invasive Surgery Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China. rsq0516@163.com.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Carcinoma, Renal CellImmune Checkpoint InhibitorsKidney NeoplasmsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2Programmed Cell Death 1 ReceptorProtein Kinase InhibitorsAnimalsCell Line, TumorCell ProliferationDrug Resistance, NeoplasmGene Expression Regulation, NeoplasticHumansInterleukin-1betaMiceImmune Checkpoint InhibitorsInterleukin-1betaLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LRRK2 protein, humanPDCD1 protein, humanProgrammed Cell Death 1 ReceptorProtein Kinase Inhibitors

Identifiers

PMID40121376

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.