title: Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors.
abstract: Inhibiting angiogenesis has become an important therapeutic strategy for cancer treatment but, like other current targeted therapies, benefits experienced for late-stage cancers can be curtailed by inherent refractoriness or by acquired drug resistance, requiring a need for better mechanistic understanding of such effects. Numerous preclinical studies have demonstrated that VEGF pathway inhibitors suppress primary tumour growth and metastasis. However, it has been recently reported that short-term VEGF and VEGFR inhibition can paradoxically accelerate tumour invasiveness and metastasis in certain models. Here we comprehensively compare the effects of both antibody and small molecule receptor tyrosine kinase (RTK) inhibitors targeting the VEGF-VEGFR pathway, using short-term therapy in various mouse models of metastasis. Our findings demonstrate that antibody inhibition of VEGF pathway molecules does not promote metastasis, in contrast to selected small molecule RTK inhibitors at elevated-therapeutic drug dosages. In particular, a multi-targeted RTK inhibitor, sunitinib, which most profoundly potentiated metastasis, also increased lung vascular permeability and promoted tumour cell extravasation. Mechanistically, sunitinib, but not anti-VEGF treatment, attenuated endothelial barrier function in culture and caused a global inhibition of protein tyrosine phosphorylation, including molecules important for maintaining endothelial cell-cell junctions. Together these findings indicate that, rather than a specific consequence of inhibiting the VEGF signalling pathway, pharmacological inhibitors of the VEGF pathway can have dose- and drug class-dependent side-effects on the host vasculature. These findings also advocate for the continued identification of mechanisms of resistance to anti-angiogenics and for therapy development to overcome it.
authors.affiliation: Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Alicia S
authors.initials: AS
authors.lastname: Chung
authors.forename: Marcin
authors.initials: M
authors.lastname: Kowanetz
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.forename: Guanglei
authors.initials: G
authors.lastname: Zhuang
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.forename: David
authors.initials: D
authors.lastname: Finkle
authors.forename: Laszlo
authors.initials: L
authors.lastname: Komuves
authors.forename: Franklin
authors.initials: F
authors.lastname: Peale
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
mesh_terms: D020533:Angiogenesis Inhibitors / Q000145:classification* / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000145:classification* / Q000627:therapeutic use*; D001549:Benzamides; D001557:Benzenesulfonates / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D007211:Indoles / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D000077157:Sorafenib; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; D004791:Enzyme Inhibitors; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib