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 regula tion of a variety of vital functions including cell proliferation, cel l differentiation, and stress response. Alteration in the expression o f 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 intr insic drug resistance associated with overexpression of the erbB-2 rec eptor. In general, tumor cells overexpressing erbB-2 are intrinsically resistant to DNA-damaging agents such as cisplatin. While the molecul ar mechanisms by which erbB-2 induces drug resistance are not yet esta blished, there is evidence that this may be a consequence of altered c ell cycle checkpoint and DNA repair mechanisms and dysregulation of ap optotic pathway(s). The apoptotic signal induced by many anticancer dr ugs originates at a receptor on the cell membrane and is transduced th rough a signaling cascade to the nucleus. Drug-induced apoptosis is de pendent on the balance between cell cycle checkpoints and DNA repair m echanisms. Blockade of erbB-2 signaling using erbB-2 antagonists, domi nant negative mutants, or chemical inhibitors of erbB-2 tyrosine kinas e activity induces cell cycle arrest: inhibits DNA repair, and (or) pr omotes apoptosis. Less understood are downstream signal transduction c ascades by which erbB-2 affects these regulatory mechanisms. The diver sity of erbB receptors results in an interconnected network of cell si gnaling pathways that determine tumor cell fate in response to chemoth erapy stress. Further investigations on the role of erbB-coupled signa ling in the regulation of stress responsive genes an critical to under stand the mechanisms by which tumor cells escape cell death, and will contribute to the development of alternative therapeutic targets to ov ercome intrinsic drug resistance in clinical settings.