title: Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade.
abstract: Anti-VEGF therapies benefit several cancer types, but drug resistance that limits therapeutic response can emerge. We generated cell lines from anti-VEGF-resistant tumor xenografts to investigate the mechanisms by which resistance develops. Of all tumor cells tested, only A431 (A431-V) epidermoid carcinoma cells developed partial resistance to the VEGF inhibitor aflibercept. Compared with the parental tumors, A431-V tumors secreted greater amounts of IL6 and exhibited higher levels of phospho-STAT3. Notably, combined blockade of IL6 receptor (IL6R) and VEGF resulted in enhanced activity against A431-V tumors. Similarly, inhibition of IL6R enhanced the antitumor effects of aflibercept in DU145 prostate tumor cells that displays high endogenous IL6R activity. In addition, post hoc stratification of data obtained from a clinical trial investigating aflibercept efficacy in ovarian cancer showed poorer survival in patients with high levels of circulating IL6. These results suggest that the activation of the IL6/STAT3 pathway in tumor cells may provide a survival advantage during anti-VEGF treatment, suggesting its utility as a source of response biomarkers and as a therapeutic target to heighten efficacious results. Cancer Res; 76(8); 2327-39. ©2016 AACR.
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Eichten
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Jia
authors.initials: J
authors.lastname: Su
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Adler
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Ella
authors.initials: E
authors.lastname: Ioffe
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Asma A
authors.initials: AA
authors.lastname: Parveen
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: John
authors.initials: J
authors.lastname: Rudge
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Hsin Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Douglas
authors.initials: D
authors.lastname: MacDonald
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Christopher
authors.initials: C
authors.lastname: Daly
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York.
authors.forename: Xunbao
authors.initials: X
authors.lastname: Duan
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York. gavin.thurston@regeneron.com.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C494086:STAT3 protein, human; C533178:aflibercept