title: Anti-EGFR therapeutic efficacy correlates directly with inhibition of STAT3 activity.
abstract: Several agents targeting the epidermal growth factor receptor (EGFR) have been FDA-approved to treat cancer patients with varying tumor types including metastatic colorectal cancer. Many patients treated with anti-EGFR therapy however do not respond and those that do initially respond often acquire resistance. Here we show a clear correlation between the efficacy of anti-EGFR inhibitors with their ability to inhibit STAT3 activity in A431 epidermoid carcinoma cells and in a series of wt K-RAS expressing human colon cancer cell lines. Furthermore, the ability of cetuximab to inhibit growth also correlated with its ability to inhibit STAT3 activity in tumor xenograft animal studies. In addition, stable knockdown of the STAT3 phosphatase, protein tyrosine phosphatase receptor delta (PTPRD) resulted in enhanced STAT3 activity and subsequent resistance to cetuximab in DIFI colon carcinoma cells. This resistance could be reversed by STAT3 inhibition. Finally, HN5 cells with acquired resistance to the EGFR tyrosine kinase inhibitor, AG1478 displayed greater STAT3 activity than the HN5 control cell line. These AG1478-refractory HN5 cells were re-sensitized to AG1478, cetuximab and erlotinib when co-treated with a STAT3 inhibitor. Taken together, our current data indicates a key role of STAT3 activity in promoting resistance to anti-EGFR therapy and suggests that anti-EGFR therapy in combination with inhibitors that block STAT3 may provide therapeutic benefit for patients with mCRC and other EGFR driven tumor types.
authors.affiliation: Department of Surgery; The University of Melbourne; The Royal Melbourne Hospital; Parkville, VIC Australia.
authors.forename: Nelson
authors.initials: N
authors.lastname: Ung
authors.affiliation: Department of Surgery; The University of Melbourne; The Royal Melbourne Hospital; Parkville, VIC Australia; Inflammation Division; Walter and Eliza Hall Institute of Medical Research; Parkville, VIC Australia; Department of Medical Biology; The University of Melbourne; Parkville, VIC Australia.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Putoczki
authors.affiliation: Department of Surgery; The University of Melbourne; The Royal Melbourne Hospital; Parkville, VIC Australia; Department of Neurosurgery; The Royal Melbourne Hospital; Parkville, VIC Australia.
authors.forename: Stanley S
authors.initials: SS
authors.lastname: Stylli
authors.affiliation: Department of Surgery; The University of Melbourne; The Royal Melbourne Hospital; Parkville, VIC Australia.
authors.forename: Irvin
authors.initials: I
authors.lastname: Ng
authors.affiliation: Ludwig Institute for Cancer Research; Austin Health; Heidelberg, VIC Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Radiation Oncology; Memorial Sloan-Kettering Cancer Center; New York, NY USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Department of Surgery; The University of Melbourne; The Royal Melbourne Hospital; Parkville, VIC Australia.
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhu
authors.affiliation: Department of Surgery; The University of Melbourne; The Royal Melbourne Hospital; Parkville, VIC Australia; Department of Medicine; The University of Melbourne; The Royal Melbourne Hospital; Parkville, VIC Australia.
authors.forename: Rodney B
authors.initials: RB
authors.lastname: Luwor
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D064593:Heterografts; D006801:Humans; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000494:pharmacology; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C101044:RTKI cpd; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D000068818:Cetuximab
keywords: EGFR; STAT3; cetuximab; colon cancer