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Cancer Res. 2016 Apr 15;76(8):2327-39. doi: 10.1158/0008-5472.CAN-15-1443. Epub 2016 Feb 26.

Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade.

Author information

1
Regeneron Pharmaceuticals, Tarrytown, New York.
2
Regeneron Pharmaceuticals, Tarrytown, New York. gavin.thurston@regeneron.com.

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.

PMID:
26921327
DOI:
10.1158/0008-5472.CAN-15-1443
[Indexed for MEDLINE]
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