title: Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression.
abstract: Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. 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.
authors.affiliation: School of Bioscience and Bioengneering, South China University of Technology, Guangzhou, China.
authors.forename: Guangchao
authors.initials: G
authors.lastname: Li
authors.affiliation: School of Bioscience and Bioengneering, South China University of Technology, Guangzhou, China.
authors.forename: Likun
authors.initials: L
authors.lastname: Zhao
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China.
authors.forename: Kexing
authors.initials: K
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China.
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China. State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China. State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China. State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, China. State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.affiliation: School of Bioscience and Bioengneering, South China University of Technology, Guangzhou, China. International Joint Cancer Institute, Second Military Medical University, Shanghai, China. State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong Provence, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008819:Mice, Nude; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D055264:Mucin-4 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000636:Aminosalicylic Acids; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D005353:Fibronectins; C508600:IL6 protein, human; D015850:Interleukin-6; C060192:MUC1 protein, human; C524658:MUC4 protein, human; D018396:Mucin-1; D055264:Mucin-4; C520337:NSC 74859; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004815:Epidermal Growth Factor; D000068878:Trastuzumab