Evaluation of Angiotensin-(1-7) as a new combination therapy to reverse resistance to VEGFR inhibitors in triple negative breast cancer

CARNEVALE, AGUSTINA; SALABERRY, PEDRO; WALTHER, THOMAS; KORDON, EDITH; GATTELLI, ALBANA; SCHERE LEVY, CAROLINA

Congreso; Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2022

In triple negative breast cancer (TNBC) the absence of targeted treatment and resistance to current therapies are crucial factors precluding improvements in mortality. Central in the mechanism of resistance is the activation of tyrosine kinase receptors, including VEGFR, the receptor for the main angiogenic factor, VEGF. VEGFR inhibitors as Axitinib (Ax) or Bevacizumab (Bev) succeed in reversing some cases but in long term, induce resistance and metastatic disease in other patients. Renin-angiotensin system has been implicated in multiple aspects of cancer progression through ACE/AngiontensinII (AngII) pathway inducing angiogenesis and metastasis. Angiotensin 1-7 [Ang-(1-7)] is generated from AngII by ACE2 enzyme. Previously, we found that AngII promotes invasion of TNBC cell lines by enhancing VEGFR signaling, and Ang-(1-7) counteracts pro-tumorigenic actions of AngII. Our group also demonstrated in renal carcinoma cells that treatment with Ax or Bev decreased ACE2 expression, and the addition of Ang-(1-7) in an in vivo combination treatment with Ax generated additive suppression of renal tumor growth and improved survival outcomes. We determined by bioinformatic tools that both ACE and ACE2 are expressed in patients with TNBC. In this study, our aim is to evaluate in vivo the effects of combined therapy of Ax + Ang-(1-7) in the treatment of TNBC. As in renal cancer, we found that treatment with Ax or Bev reduces ACE2 expression (p