Estudio de mecanismos de resistencia a terapias anti HER2 en cáncer de mama

SCHILLACI R

Seminario; Seminario Institucional en IQUIFIB; 2017

IQUIFIB

Purpose: Although trastuzumab administration improved theoutcome of HER2-positive breast cancer patients, resistanceevents hamper its clinical benefits. We demonstrated that TNFastimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanismof TNFa-induced trastuzumab resistance and the therapeuticstrategies to overcome it.Experimental Design: Trastuzumab-sensitive breast cancercells, genetically engineered to stably overexpress TNFa, andde novo trastuzumab-resistant tumors, were used to evaluatetrastuzumab response and TNFa-blocking antibodies effectivenessrespectively. Immunohistochemistry and antibody-dependentcell cytotoxicity (ADCC), together with siRNA strategy,were used to explore TNFa influence on the expression andfunction of its downstream target, mucin 4 (MUC4). Theclinical relevance of MUC4 expression was studied in a cohortof 78 HER2-positive breast cancer patients treated with adjuvanttrastuzumab.Results: TNFa overexpression turned trastuzumab-sensitivecells and tumors into resistant ones. Histopathologic findingsrevealed mucin foci in TNFa-producing tumors. TNFa inducedupregulation of MUC4 that reduced trastuzumab binding to itsepitope and impaired ADCC. Silencing MUC4 enhanced trastuzumabbinding, increased ADCC, and overcame trastuzumab andtrastuzumab-emtansine antiproliferative effects in TNFa-overexpressingcells. Accordingly, administration of TNFa-blockingantibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. InHER2-positive breast cancer samples, MUC4 expression wasfound to be an independent predictor of poor disease-free survival(P ¼ 0.008).Conclusions: We identified TNFa-induced MUC4 expressionas a novel trastuzumab resistance mechanism. We proposeMUC4expression as a predictive biomarker of trastuzumab efficacy and aguide to combination therapy of TNFa-blocking antibodies withtrastuzumab.