2. Academic Validation
  3. Preoperative neoadjuvant targeted therapy remodels intra-tumoral heterogeneity of clear-cell renal cell carcinoma and ferroptosis inhibition induces resistance progression

Preoperative neoadjuvant targeted therapy remodels intra-tumoral heterogeneity of clear-cell renal cell carcinoma and ferroptosis inhibition induces resistance progression

  • Cancer Lett. 2024 Jul 1:593:216963. doi: 10.1016/j.canlet.2024.216963.
Wen-Jin Chen 1,  Xiu-Wu Pan 2,  Xu Song 3,  Zi-Chang Liu 4,  Da Xu 5,  Jia-Xin Chen 6,  Ke-Qin Dong 7,  Si-Chen Di 8,  Jian-Qing Ye 9,  Si-Shun Gan 10,  Lin-Hui Wang 11,  Wang Zhou 12,  Xin-Gang Cui 13
Affiliations

Affiliations

  • 1 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China; Depanrtment of Urology, Third Affiliated Hospital of the Naval Medical University, Shanghai, 201805, China. Electronic address: chenwenjin@smmu.edu.cn.
  • 2 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: panxiuwu@126.com.
  • 3 Department of Urology, Shanghai Seventh People's Hospital, Shanghai, 200137, China. Electronic address: 1418855811@qq.com.
  • 4 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: liuzichang1125@gmail.com.
  • 5 Depanrtment of Urology, Third Affiliated Hospital of the Naval Medical University, Shanghai, 201805, China. Electronic address: xuda@smmu.edu.cn.
  • 6 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: jiaxinchan@smmu.edu.cn.
  • 7 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: keqindong_0125@163.com.
  • 8 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: disichen372@163.com.
  • 9 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: ye910@126.com.
  • 10 Depanrtment of Urology, Third Affiliated Hospital of the Naval Medical University, Shanghai, 201805, China. Electronic address: gansishun20101111@163.com.
  • 11 Department of Urology, Changhai Hospital of Naval Medical University, 168 Changhai Road, Shanghai, 200433, China. Electronic address: wanglinhui@smmu.edu.cn.
  • 12 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: brilliant212@163.com.
  • 13 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China; Depanrtment of Urology, Third Affiliated Hospital of the Naval Medical University, Shanghai, 201805, China. Electronic address: cuixingang@xinhuamed.com.cn.
PMID: 38768682 DOI: 10.1016/j.canlet.2024.216963
Abstract

Neoadjuvant tyrosine kinase inhibitor (TKI) therapy is an important treatment option for advanced renal cell carcinoma (RCC). Many RCC patients may fail to respond or be resistant to TKI therapy. We aimed to explore the key mechanisms of neoadjuvant therapy résistance. We obtained tumor samples from matched pre-treatment biopsy and post-treatment surgical samples and performed single-cell RNA Sequencing. Sunitinib-resistant ccRCC cell lines were established. Ferroptosis was detected by ferrous ion and lipid peroxidation levels. Tumor growth and resistance to Sunitinib was validated in vitro and vivo. Immunohistochemistry was used to validate the levels key genes and lipid peroxidation. Multi-center cohorts were included, including TCGA, ICGC, Checkmate-025 and IMmotion151 clinical trial. Survival analysis was performed to identify the associated clinical and genomic variables. Intratumoral heterogeneity was first described in the whole neoadjuvant management. The signature of endothelial cells was correlated with drug sensitivity and progression-free survival. Ferroptosis was shown to be the key biological program in malignant cell resistance. We observed tissue lipid peroxidation was negatively correlated with IL6 and tumor response. TKI-resistant cell line was established. SLC7A11 knockdown promoted cell growth and lipid peroxidation, increased the Ferroptosis level, and suppressed the growth of tumor xenografts significantly (P < 0.01). IL6 could reverse the Ferroptosis and malignant behavior caused by SLC7A11 (-) via JAK2/STAT3 pathway, which was rescued by the Ferroptosis inducer Erastin. Our data indicate that Ferroptosis is a novel strategy for advanced RCC treatment, which activated by IL6, providing a new idea for resistance to TKIs.

Keywords

Clear-cell renal cell carcinoma; Drug resistance; Ferroptosis; Neoadjuvant therapy; Tyrosine kinases inhibitors.

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