Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma

Shuhei Kamada, Takeshi Namekawa, Kazuhiro Ikeda, Takashi Suzuki, Makoto Kagawa, Hideki Takeshita, Akihiro Yano, Koji Okamoto, Tomohiko Ichikawa, Kuniko Horie-Inoue, Satoru Kawakami, Satoshi Inoue

Research output: Contribution to journalArticlepeer-review

Abstract

Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases eventually progress by acquiring resistance. Cancer stemness plays critical roles in tumor aggressiveness and therapeutic resistance, and dipeptidyl peptidase IV (DPP4) has been recently identified as a cancer stemness-related protein. A question arises whether DPP4 contributes to TKI efficacy in RCC. We established patient-derived RCC spheroids and showed that DPP4 expression is associated with stemness-related gene expression. TKI sunitinib resistance was rescued by DPP4 inhibition using sitagliptin or specific siRNAs in RCC cells and tumors. DPP4 expression can be inducible by retinoic acid and repressed by ALDH1A inhibition. Among type 2 diabetes patients with clinical RCC tumors, higher TKI efficacy is observed in those bearing DPP4high tumors treated with DPP4 inhibitors. This study provides new insights into TKI resistance and drug repositioning of DPP4 inhibitor as a promising strategy for advanced RCC.

Original languageEnglish
Pages (from-to)3899-3913
Number of pages15
JournalOncogene
Volume40
Issue number22
DOIs
Publication statusPublished - 2021 Jun 3
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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