title: Overcoming resistance of targeted EGFR monotherapy by inhibition of STAT3 escape pathway in soft tissue sarcoma.
abstract: Although epidermal growth factor receptor (EGFR) is often over-expressed in soft tissue sarcoma (STS), a phase II trial using an EGFR inhibitor gefitinib showed a low response rate. This study identified a new secondary resistance mechanism of gefitinib in STS, and developed new strategies to improve the effectiveness of EGFR inhibition particularly by blocking the STAT3 pathway.We demonstrated that seven STS cell lines of diverse histological origin showed resistance to gefitinib despite blockade of phosphorylated EGFR (pEGFR) and downstream signal transducers (pAKT and pERK) in PI3K/AKT and RAS/ERK pathways. Gefitinib exposure was not associated with decrease in the ratio of pSTAT3/pSTAT1. The relative STAT3 abundance and activation may be responsible for the drug resistance. We therefore hypothesized that the addition of a STAT3 inhibitor could overcome the STAT3 escape pathway.We found that the addition of STAT3 inhibitor S3I-201 to gefitinib achieved synergistic anti-proliferative and pro-apoptotic effects in all three STS cell lines examined. This was confirmed in a fibrosarcoma xenografted mouse model, where the tumours from the combination group (418mm3) were significantly smaller than those from untreated (1032mm3) or single drug (912 and 798mm3) groups.Our findings may have clinical implications for optimising EGFR-targeted therapy in STS.
authors.affiliation: Department of Surgery, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.|Sarcoma and Nanooncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Department of Surgery, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.|Sarcoma and Nanooncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Crowe
authors.affiliation: Sarcoma and Nanooncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Yang
authors.affiliation: Bendat Family Comprehensive Cancer Centre, St John of God HealthCare, Perth, Australia.|School of Surgery, The University of Western Australia, Perth, Australia.
authors.forename: Kerryn
authors.initials: K
authors.lastname: Garrett
authors.affiliation: Bendat Family Comprehensive Cancer Centre, St John of God HealthCare, Perth, Australia.|School of Surgery, The University of Western Australia, Perth, Australia.
authors.forename: Nikolajs
authors.initials: N
authors.lastname: Zeps
authors.affiliation: Department of Surgery, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.|Sarcoma and Nanooncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Clinical School of Prince of Wales Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Yang
mesh_terms: D000636:Aminosalicylic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C520337:NSC 74859; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR; STAT3; resistance; sarcoma; targeted therapy