Science and Technology Production
Congress
Authorship
Bruni S
;
De Martino M
;
Proietti, C
;
Martin A. Rivas
;
Elizalde PV
;
SCHILLACI, ROXANA
;
Mercogliano MF
Date
2017
Publishing House and Editing Place
Sigma
Summary
Information provided by the agent in
SIGEVA
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 monoclonal cancer (BC) patients. They receive trastuzumab (T), an anti-HER2monoclonal antibody, but resistance event...
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 monoclonal cancer (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 monoclonalantibody 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<0.05). Proliferation of cells treated with IgG, T, P, DN,E (10 μg/ml, 10 μg/ml, 10 μg/ml, 2 μg/ml and 5 μg/ml respectively)as monotherapy and in different combinations was evaluated bycell count or [3H]-thymidine incorporation. The combination of TNFαblockade with T+P inhibited cell proliferation vs. IgG, P+T, P+E,P+DN (p<0.0001). In spite of these results, indirect immunofluorescenceand flow cytometry analysis proved that P binding was lowerin E and DN treated cells vs. IgG treated cells (p<0.01). Similarresults were obtained using MUC4 siRNA, suggesting that MUC4has a controversial role in T+P resistance, which is being investigated.These results suggest that TNFα blockade could overcomeT+P resistance in HER2+ BC. Moreover, patients with expressionof TNFα and MUC4 could be eligible for a combination therapy withTNFα-blocking agents to overcome/avoid resistance to therapy.
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Key Words
TNFpertuzumabtrastuzumabHER2