The role of ErbB-2 tyrosine kinase receptor in cellular intrinsic chemoresistance: mechanisms and implications.
The erbB family of tyrosine kinase receptors is involved in the regulation of a variety of vital functions including cell proliferation, cell differentiation, and stress response. Alteration in the expression of erbB receptors occurs in numerous tumor types and plays an important role in cancer development, cancer progression, and susceptibility to cell killing by anticancer agents. Of particular interest is the intrinsic drug resistance associated with overexpression of the erbB-2 receptor. In general, tumor cells overexpressing erbB-2 are intrinsically resistant to DNA-damaging agents such as cisplatin. While the molecular mechanisms by which erbB-2 induces drug resistance are not yet established, there is evidence that this may be a consequence of altered cell cycle checkpoint and DNA repair mechanisms and dysregulation of apoptotic pathway(s). The apoptotic signal induced by many anticancer drugs originates at a receptor on the cell membrane and is transduced through a signaling cascade to the nucleus. Drug-induced apoptosis is dependent on the balance between cell cycle checkpoints and DNA repair mechanisms. Blockade of erbB-2 signaling using erbB-2 antagonists, dominant negative mutants, or chemical inhibitors of erbB-2 tyrosine kinase activity induces cell cycle arrest, inhibits DNA repair, and (or) promotes apoptosis. Less understood are downstream signal transduction cascades by which erbB-2 affects these regulatory mechanisms. The diversity of erbB receptors results in an interconnected network of cell signaling pathways that determine tumor cell fate in response to chemotherapy stress. Further investigations on the role of erbB-coupled signaling in the regulation of stress responsive genes are critical to understand the mechanisms by which tumor cells escape cell death, and will contribute to the development of alternative therapeutic targets to overcome intrinsic drug resistance in clinical settings.
Alaoui-Jamali
M A
MA
Lady Davis Institute of the Sir Mortimer B. Davis Jewish General Hospital, Department of Medicine, McGill University, Montréal, QC, Canada. mdaj@musica.mcgill.ca
Paterson
J
J
Al Moustafa
A E
AE
Yen
L
L
D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*
D018719:Erb-b2 Receptor Tyrosine Kinases