Abstract
The majority of patients develop resistance against suppression of HER2-signaling mediated 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. Using 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 restricted to markers significantly associated with worse survival. Functional significance of the two strongest predictive markers was evaluated in vitro by gene silencing in HER2 overexpressing, trastuzumab resistant BC cell lines SKTR and JIMT-1. The strongest predictive MKPs were DUSP4/MKP-2 (AUC=0.75, p=0.0096) and DUSP6/MKP-3 (AUC=0.77, p=5.29E-05). Higher expression for these correlated to worse survival (DUSP4: HR=2.05, p=0.009 and DUSP6: HR=2, p=0.0015). Silencing of DUSP4 had significant sensitization effects – viability of DUSP4 siRNA transfected, trastuzumab treated cells decreased significantly compared to scramble-siRNA transfected controls (SKTR: p=0.016; JIMT-1: p=0.016). In contrast, simultaneous treatment with DUSP6 siRNA and trastuzumab did not alter cell proliferation. Our findings suggest that DUSP4 may represent a new potential target to overcome trastuzumab resistance.
Highlights
Human epidermal growth factor receptor 2 (HER2) is a critical member of the epidermal growth factor receptor (EGFR) transmembrane receptor tyrosine kinase (RTK) family
DUSP4/MAPK phosphatases (MKPs)-2 and DUSP6/MKP-3, in silico identified candidate MKPs associated with survival, were validated in vitro in HER2-overexpressing trastuzumabresistant cell lines
The mitogen-activated protein kinase (MAPK) signaling pathway is a key transducer of growth factor signaling that incorporates three family members: the extracellular signal regulated kinases (ERK), the c-Jun N-terminal kinases (JNK), and the p38 MAPKs
Summary
Human epidermal growth factor receptor 2 (HER2) is a critical member of the epidermal growth factor receptor (EGFR) transmembrane receptor tyrosine kinase (RTK) family. The introduction of the anti-HER2 monoclonal antibody trastuzumab in 1998 transformed the course of disease for these patients, and today HER2-positivity confers better prognosis compared to receptor negativity [8]. Trastuzumab is a humanized monoclonal antibody (mAb) that attaches to the fourth extracellular domain of the HER2 receptor suppressing HER2 signaling. Trastuzumab improves objective response rate (ORR), progression free survival (PFS) and overall survival (OS) of HER2-positive patients [9]. It provides advantage for disease-free survival (DFS) and OS as adjuvant therapy combined with chemotherapy [10, 11], or as monotherapy after chemotherapy [12]. Neoadjuvant trastuzumab combined with chemotherapy improved pathologic complete remission (pCR) in phase II and III clinical trials [14]
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