2. Academic Validation
  3. PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-β pathway

PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-β pathway

  • Br J Cancer. 2024 May 31. doi: 10.1038/s41416-024-02725-4.
Haibo Wang # 1 2 3,  Lijie Zhang # 4,  Hua Liu 1,  Yumeng Yang 1,  Wenxiu Lu 1,  Xuedi Cao 1,  Xiaomei Yang 1 3,  Qiong Qin 1 3,  Ran Song 1 3,  Duiping Feng 5,  Songlin Wang 1 2 6,  Tao Bai 7,  Junqi He 8 9
Affiliations

Affiliations

  • 1 Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, People's Republic of China.
  • 2 Beijing Laboratory of Oral Health, Capital Medical University, Beijing, People's Republic of China.
  • 3 Laboratory for Clinical Medicine, Capital Medical University, Beijing, People's Republic of China.
  • 4 Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People's Republic of China.
  • 5 Department of Interventional Radiology, First Hospital of Shanxi Medical University, Taiyuan, People's Republic of China.
  • 6 Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy and Tooth Regeneration, School of Stomatology, Capital Medical University, Beijing, People's Republic of China.
  • 7 Department of Pathology, First Hospital of Shanxi Medical University, Taiyuan, People's Republic of China. 13703515398@163.com.
  • 8 Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, People's Republic of China. jq_he@ccmu.edu.cn.
  • 9 Laboratory for Clinical Medicine, Capital Medical University, Beijing, People's Republic of China. jq_he@ccmu.edu.cn.
  • # Contributed equally.
PMID: 38822145 DOI: 10.1038/s41416-024-02725-4
Abstract

Background: Sunitinib has emerged as the primary treatment for advanced or metastatic clear cell renal cell carcinoma (ccRCC) due to its significant improvement in patients' average survival time. However, drug resistance and adverse effects of sunitinib pose challenges to its clinical benefits.

Methods: The differentially expressed genes (DEGs) associated with sunitinib sensitivity and resistance in ccRCC were investigated. Cell counting kit-8, plate colony formation, flow cytometry and subcutaneous xenograft tumor model assays were employed to explore the effects of PDZK1 on ccRCC. Further research on the molecular mechanism was conducted through western blot, co-immunoprecipitation, immunofluorescence co-localization and immunohistochemical staining.

Results: We elucidated that PDZK1 is significantly downregulated in sunitinib-resistant ccRCC specimens, and PDZK1 negatively regulates the phosphorylation of PDGFR-β and the activation of its downstream pathways through interaction with PDGFR-β. The dysregulated low levels of PDZK1 contribute to inadequate inhibition of cell proliferation, tumor growth, and insensitivity to sunitinib treatment. Notably, our preclinical investigations showed that miR-15b antagomirs enhance sunitinib cytotoxic effects against ccRCC cells by upregulating PDZK1 levels, suggesting their potential in overcoming sunitinib resistance.

Conclusions: Our findings establish the miR-15b/PDZK1/PDGFR-β axis as a promising therapeutic target and a novel predictor for ccRCC patients' response to sunitinib treatment.

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