ACE2 downregulation as a resistance mechanism to VEGFR-tyrosine kinase inhibitor (VEGFR-TKI) treatment in breast cancer therapy

CARNEVALE AGUSTINA; WALTHER T.; EDITH KORDON; ALBANA GATTELLI; SCHERE-LEVY, CAROLINA

CABA

Simposio; BA-BCS 2021; 2021

Absence of effective treatment and tumor resistanceto current therapies for triple negative breast cancer(TNBC) are crucial factors. Central in the mechanismof resistance is overexpression/activation of tyrosinekinase receptor (RTK). Inhibitors targeting RTKs, includingVEGFR, induce resistance and metastatic diseasein some patients. Renin Angiotensin (Ang) system hasbeen implicated in cancer progression through ACE1/AngII inducing angiogenesis and metastasis. Ang-(1-7),is generated from AngII by ACE2. Previously, we foundthat AngII promotes invasion by activating VEGFR signalingin TNBC and Ang-(1-7) counteracts undesirableactions of AngII. Besides, it has been demonstrated thatVEGFR-TKI treatment of renal carcinoma decreasedACE2 expression, and combination treatment with VEG -FR-TKI and Ang-(1-7) generated additive suppressionof tumor growth and survival outcomes. Here, we foundthat treatment with Axitinib or Bevacizumab significantlyreduced ACE2 expression in two metastatic TNBC-likebreast cancer cell lines (MB-MDA231 & EO771). Interestingly,this treatment did not alter ACE2 expressionin a non-metastatic cell line (T47D), suggesting thatthis is a mechanism operating in a more aggressivephenotype. In contrast, we found an increase in ACE1expression in RTK-driven tumor model. We suggest thatthe balance of ACE1/ACE2 expression could serve asan indicator of tumor malignancy and therapy resistanceand we propose a preclinical breast cancer model totarget ACE2/Ang-(1-7) axis.