title: Sunitinib Treatment Enhances Metastasis of Innately Drug-Resistant Breast Tumors.
abstract: Antiangiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date, there has not been an inquiry into the 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 antiangiogenic 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.Cancer Res; 77(4); 1008-20. ©2016 AACR.
authors.affiliation: Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Wragg
authors.affiliation: Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Heath
authors.affiliation: Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom. r.bicknell@bham.ac.uk.
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D051398:Aquaporin 1 / Q000502:physiology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology; D002465:Cell Movement; D016207:Cytokines / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008163:Luminescent Measurements; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D016207:Cytokines; D007211:Indoles; D011758:Pyrroles; C066845:pleiotrophin; D051398:Aquaporin 1; D000077210:Sunitinib