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

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.

• Authors: Prateek Khanna, Hong Jie Soh, Chun-Hau Chen, Ruchi Saxena, Seema Amin, Maura Naughton, Patrick Neset Joslin, Andrew Moore, Ziad Bakouny, Carol O'Callaghan, Paul Catalano, Sabina Signoretti, Rana McKay, Toni K Choueiri, Manoj Bhasin, Thomas Walther, Rupal S Bhatt
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 577 (01 20 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33472951 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Peptide Fragments
• Protein Kinase Inhibitors
• Vascular Endothelial Growth Factor A
• Angiotensin II
• Angiotensin I
• Peptidyl-Dipeptidase A
• Angiotensin-Converting Enzyme 2
• angiotensin I (1-7)

Topics

• Angiotensin I
• Angiotensin II
• Angiotensin-Converting Enzyme 2
• Animals
• Carcinoma, Renal Cell (drug therapy)
• Humans
• Kidney Neoplasms (drug therapy)
• Peptide Fragments
• Peptidyl-Dipeptidase A
• Protein Kinase Inhibitors
• Vascular Endothelial Growth Factor A