Research ArticleCancer

ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma

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Science Translational Medicine  20 Jan 2021:
Vol. 13, Issue 577, eabc0170
DOI: 10.1126/scitranslmed.abc0170

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An ACE2 in the hole

Clear cell renal cell carcinoma (ccRCC) is a form of kidney cancer commonly treated with agents targeting vascular endothelial growth factor (VEGF) signaling; however, resistance develops. Cotreatment with inhibitors of angiotensin signaling can improve survival, so Khanna et al. focused on the role of angiotensin converting enzyme 2 (ACE2), a natural antagonist of classical angiotensin signaling. Higher expression of ACE2 correlated with better survival in patients with ccRCC, and overexpression of ACE2 inhibited tumor colony formation. Combining angiotensin-(1-7), a cleavage product of ACE2, with VEGF inhibition provided greater antitumor effects than VEGF inhibition alone, suggesting a potential therapy for ccRCC.

Abstract

Angiotensin converting enzyme 2 (ACE2) is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) receptor pathway. Here, we report that higher ACE2 expression correlates with better overall survival in patients with clear cell renal cell carcinoma (ccRCC). Moreover, ACE2 has inhibitory effects on tumor proliferation in ccRCC in vitro and in preclinical animal models of ccRCC. We further show that Ang-(1-7), a heptapeptide generated by ACE2, is the likely mediator of this effect. Vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI) treatment of ccRCC xenografts decreased ACE2 expression, and combination treatment with VEGFR-TKI and Ang-(1-7) generated additive suppression of tumor growth and improved survival outcomes. Last, the addition of Ang-(1-7) to programmed death-ligand 1 (PD-L1) pathway inhibitor and VEGFR-TKI showed further growth suppression in an immunocompetent RCC model. Together, these results suggest that targeting the ACE2/Ang-(1-7) axis is a promising therapeutic strategy against ccRCC.

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