Abstract P5-08-22: DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer

Abstract

Abstract Background. The majority of patients develop resistance against suppression of HER2-mediated signaling by trastuzumab in HER2 positive breast cancer (BC). HER2 overexpression activates multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade. MAPK phosphatases (MKPs) are essential regulators of MAPKs and participate in many facets of cellular regulation, including proliferation and apoptosis. We aimed to identify whether differential MKPs are associated with resistance to targeted therapy in patients previously treated with trastuzumab. Methods. Using Affymetrix HGU133plus2 gene chip data of 88 HER2-positive, trastuzumab treated BC patients, candidate MKPs were identified by Receiver Operator Characteristics analysis performed in R. Genes were ranked using their achieved area under the curve (AUC) values and were further constricted to those markers significantly associated to worse survival. Functional significance of the two strongest predictive biomarkers was evaluated in vitro experiments after gene silencing in the HER2 overexpressing, trastuzumab resistant breast cancer cell lines SKBR-3-TR and JIMT-1. Results. Out of 10 investigated MKPs, the strongest predictive genes were DUSP4/MKP2 (AUC=0.75, p=0.0096) and DUSP6/MKP3 (AUC=0.77, p=5.29E-05). Furthermore, higher expression for these correlated to worse survival in 221 HER2 positive BC patients (DUSP4: HR=1.6, p=0.04 and DUSP6: HR=1.8, p=0.0053). Silencing of DUSP4 had significant sensitization effects - viability of DUSP4 siRNA transfected, trastuzumab treated cells decreased significantly compared to scramble-siRNA transfected, trastuzumab treated controls (SKBR-3-TR: p=0.016; JIMT-1: p=0.016). In contrast, simultaneous treatment with DUSP6 siRNA and trastuzumab did not alter cell proliferation. Conclusions. Our findings suggest that DUSP4 is involved in the development of trastuzumab resistance in HER2 positive BC. Citation Format: Györffy B, Munkacsy G, Esteva FJ, Miquel TP, Menyhart O. DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-22.