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

Agustina Florencia Carnevale¹, Thomas Walther², Edith Kordon¹, Albana Gatelli¹, Carolina Schere-Levy¹

Absence of effective treatment and tumor resistance to current therapies for triple negative breast cancer (TNBC) are crucial factors. Central in the mechanism of resistance is overexpression/activation of tyrosine kinase receptor (RTK). Inhibitors targeting RTKs, including VEGFR, induce resistance and metastatic disease in some patients. Renin Angiotensin (Ang) system has been implicated in cancer progression through ACE1/AngII inducing angiogenesis and metastasis. Ang-(1-7), is generated from AngII by ACE2. Previously, we found that AngII promotes invasion by activating VEGFR signaling in TNBC and Ang-(1-7) counteracts undesirable actions of AngII. Besides, it has been demonstrated that VEGFR-TKI treatment of renal carcinoma decreased ACE2 expression, and combination treatment with VEGFR-TKI and Ang-(1-7) generated additive suppression of tumor growth and survival outcomes. Here, we found that treatment with Axitinib or Bevacizumab significantly reduced ACE2 expression in two metastatic TNBC-like breast cancer cell lines (MB-MDA231 & EO771). Interestingly, this treatment did not alter ACE2 expression in a non-metastatic cell line (T47D), suggesting that this is a mechanism operating in a more aggressive phenotype. In contrast, we found an increase in ACE1 expression in RTK-driven tumor model. We suggest that the balance of ACE1/ACE2 expression could serve as an indicator of tumor malignancy and therapy resistance and we propose a preclinical breast cancer model to target ACE2/Ang-(1-7) axis.