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

MARA DE MARTINO; SOFIA BRUNI; PATRICIA V ELIZALDE; CECILIA J PROIETTI; MARTIN RIVAS; ROXANA SCHILLACI; FLORENCIA MERCOGLIANO

Congreso; LXII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2017

HER2 positive (HER2+) is a subtype that affects 13-20% of breastcancer (BC) patients. They receive trastuzumab (T), an anti-HER2monoclonal antibody, but resistance events hamper its clinical benefitin 40-60% of the cases. We demonstrated that TNFα overexpressionturned T-sensitive cells and tumors into resistant ones byupregulating mucin 4 (MUC4) expression. Pertuzumab (P, a monomonoclonalantibody that disrupts HER2/HER3 dimerization) is anotheranti-HER2 therapy that is used in combination with T. The aim ofthis work was to explore whether TNFα and TNFα-induced MUC4expression play a role in the resistance to the combination therapyT+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 establishedJIMT-1 tumors in female nude mice to explore whetherTNFα blockade overcomes T+P resistance. Animals were treatedwith 5 mg/kg of IgG, P, T+P, 10 mg/kg of DN or P+T+DN i.p. twice aweek. The combination of T+P+DN inhibited tumor growth vs. T+Por P+DN (p