Sunitinib treatment enhances metastasis of innately drug resistant breast tumors

Research output: Contribution to journalArticle

Abstract

Anti-angiogenic therapies have failed to confer survival benefits in patients with
metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications.

Details

Original languageEnglish
Pages (from-to)1008-1020
Number of pages12
JournalCancer Research
Volume77
Issue number4
Early online date23 Dec 2016
Publication statusPublished - 1 Feb 2017