ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside.
Tyrosine Kinase Inhibitors (TKI) have significantly changed the landscape of current cancer therapy. Understanding of mechanisms of aberrant TK signaling and strategies to inhibit TKs in cancer, further promote the development of novel agents.ABT-869, a novel ATP-competitive receptor tyrosine kinase inhibitor is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor families. ABT-869 showed potent antiproliferative and apoptotic properties in vitro and in animal cancer xenograft models using tumor cell lines that were "addicted" to signaling of kinases targeted by ABT-869. When given together with chemotherapy or mTOR inhibitors, ABT-869 showed at least additive therapeutic effects. The phase I trial for ABT-869 was recently completed and it demonstrated respectable efficacy in solid tumors including lung and hepatocellular carcinoma with manageable side effects. Tumor cavitation and reduction of contrast enhancement after ABT-869 treatment supported the antiangiogenic activity. The correlative laboratory studies conducted with the trial also highlight potential biomarkers for future patient selection and treatment outcome.Parallel to the clinical development, in vitro studies on ABT-869 resistance phenotype identified novel resistance mechanism that may be applicable to other TKIs. The future therapeutic roles of ABT-869 are currently been tested in phase II trials.
Zhou
Jianbiao
J
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. mdczjb@nus.edu.sg
Goh
Boon-Cher
BC
Albert
Daniel H
DH
Chen
Chien-Shing
CS
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D007938:Leukemia / Q000188:drug therapy; D008954:Models, Biological; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C513486:linifanib; D011505:Protein-Tyrosine Kinases