Functional Inhibition of Cancer Stemness-related Protein DPP4 Rescues Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2021 May 11

PMID 33972682

Citations 9

Authors

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

Affiliations

Soon will be listed here.

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 DPP4 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.

Citing Articles

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