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.
Science translational medicine. 2021 Jan 20 [Epub]
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
Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Division of Interdisciplinary Medicine and Biotechnology and Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland. ., Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. .