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

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.

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Fig. 1: Correlation analysis between expression levels of DPP4 and cancer stemness-related genes in patient-derived renal cell carcinoma (RCC) spheroid cultures.
Fig. 2: DPP4 inhibition enhances tumor-suppressive efficacy of tyrosine kinase inhibitor sunitinib in patient-derived renal cell carcinoma (RCC) spheroid cultures.
Fig. 3: DPP4 inhibition enhances sunitinib efficacy in three-dimensional (3D) cultures of sunitinib-resistant renal cell carcinoma (RCC) cells whereas DPP4 overexpression rescues sunitinib-dependent repression of cell viability in RCC cells.
Fig. 4: Retinoic acid signaling modulates DPP4 expression in renal cell carcinoma (RCC) cells.
Fig. 5: Sitagliptin overcomes sunitinib resistance in xenograft tumors derived from ACHN cells.
Fig. 6: DPP4 inhibitor therapy potentially improves prognosis and tumor regression of renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKIs).

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All other data are available in the Article, Supplementary Information or available from the authors upon reasonable request.

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Acknowledgements

We thank S. Kitayama, W. Sato, S. Shiba, Y. Okada, and S. Aoki for their technical support and valuable comments. This study was supported by the Support Project of Strategic Research Center in Private Universities from the MEXT (to SI), the Practical Research for Innovative Cancer Control (JP18ck0106194 to KI) and the Project for Cancer Research and Therapeutic Evolution (P-CREATE, JP18cm0106144 to SI) from Japan Agency for Medical Research and Development (AMED), and grants from the Japan Society for the Promotion of Science (15K15353 and 20K21667 to SI, and 17H04205 to K-HI) and the Vehicle Racing Commemorative Foundation (to K-HI).

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Study concepts: KI, KH-I, KO, SI. Study design: KI, KH-I, KO, SI. Data acquisition: MK, HT, AY, SK, KI. Quality control of data and algorithms: SK, TN, KO, KI, KH-I. Data analysis and interpretation: SK, TS, KI. Statistical analysis: SK, TS, KI. Paper preparation: SK, KI, KH-I, Inoue S. Paper editing: SK, KI, KH-I, TN, TS. Paper review: KO, TI, AY, SK, SI.

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Correspondence to Satoshi Inoue.

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Kamada, S., Namekawa, T., Ikeda, K. et al. Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma. Oncogene 40, 3899–3913 (2021). https://doi.org/10.1038/s41388-021-01822-5

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