TNFα BLOCKADE OVERCOMES TRASTUZUMAB AND PERTUZUMAB RESISTANCE IN HER2 POSITIVE BREAST CANCER

BRUNI, SOFIA; DE MARTINO, MARA; PROIETTI, CECILIA JAZMÍN; RIVAS, MARTÍN ALFREDO; ELIZALDE, PATRICIA V.; SCHILLACI, ROXANA; MERCOGLIANO, MARÍA FLORENCIA

CABA

Congreso; Reunión conjunta de sociedades de biociencias, LXII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

Sociedad Argentina de Investigación Clínica (SAIC)

HER2 positive (HER2+) is a subtype that affects 13-20% of breast cancer (BC) patients. They receive trastuzumab (T), an anti-HER2 monoclonal antibody, but resistance events hamper its clinical benefit in 40-60% of the cases. We demonstrated that TNFα overexpression turned T-sensitive cells and tumors into resistant ones by upregulating mucin 4 (MUC4) expression. Pertuzumab (P, a monoclonal antibody that disrupts HER2/HER3 dimerization) is another anti-HER2 therapy that is used in combination with T. The aim of this work was to explore whether TNFα and TNFα-induced MUC4 expression play a role in the resistance to the combination therapy T+P. Our approach consisted in blocking TNFα, either with Etanercept (E) or the dominant negative protein XProTM1595 (DN) in JIMT-1, de novo T+P resistant cell line which produces TNFα. We established JIMT-1 tumors in female nude mice to explore whether TNFα blockade overcomes T+P resistance. Animals were treated with 5 mg/kg of IgG, P, T+P, 10 mg/kg of DN or P+T+DN i.p. twice a week. The combination of T+P+DN inhibited tumor growth vs. T+P or P+DN (p