Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions.
Aberrant activation of HER2 through overexpression has been shown to play an important role in some breast cancers. Therapies against this receptor including the monoclonal antibody, trastuzumab, or the small tyrosine kinase inhibitor, lapatinib have shown to improve the prognosis of such patients. Despite overexpressing HER2, some patients do not respond to these targeted treatments or progress after a short period of time. Irreversible tyrosine kinase inhibitors have been developed to bypass several pathways that could be involved in this resistance. In vitro, these agents have been shown to be more potent and to prolong target inhibition. Clinical development of these agents is ongoing and early results are promising. This review will describe the biologic rationale that justifies the development of these agents in breast cancer focusing on the current status and future directions.
Ocaña
Alberto
A
Drug Development Program, Princess Margaret Hospital, Toronto, Canada M5G 2M9. alberto.ocana@uhn.on.ca
Amir
Eitan
E
D000077716:Afatinib; D000634:Aminoquinolines / Q000627:therapeutic use; D000814:Aniline Compounds / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005544:Forecasting; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077341:Lapatinib; D009025:Morpholines / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D000068878:Trastuzumab; D015854:Up-Regulation
D000634:Aminoquinolines; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D000077341:Lapatinib; D000077716:Afatinib; C420268:Canertinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C487932:neratinib; D000068878:Trastuzumab; C413879:EKB 569