Feedback Activation Of STAT3 Mediates Trastuzumab Resistance Via Upregulation Of MUC1 And MUC4 Expression

The anti-human epidermal growth factor receptor 2(HER2) antibody trastuzumab is approved by Food and Drug Administration(FDA) for therapy of patients with HER-overexpressing breast and gastric cancer. However, a quite fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective. Therefore, overcoming trastuzumab resistance and subsequently exploring effective treatment strategies remain a large unmet need in clinic.In this study, we have revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. We have previously established two sub-cell lines, which were examined to be highly resistant to trastuzumab in vitro and in vivo. Further analysis revealed a highly activated STAT3 in both acquired resistant sub-cell lines, and similar findings in the primary resistant cells mediated by PTEN deficiency. Silencing STAT3 with specific small interfering RN A(siRNA) dramatically rescued the sens itivity of resistant cells to trastuzumab. We also found that chronic exposure of trastuzumab causes the upregulation of fibronection(FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells, and these heterogeneous upstream mediators converge in STAT3 hyperactivation, which promotes the expression of MUC1 and MUC4, two known target genes of STAT3 capable of mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Furthermore, activated STAT3 enhances the expression of FN, EGF and IL-6, therefore constituting a positive feedback loop which amplifies and maintains the STAT3 signal. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo.Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance.Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.