CISPLATIN RESISTANCE IN CYCLIC-AMP-DEPENDENT PROTEIN-KINASE MUTANTS

The emergence of cisplatin resistance poses a major problem to the suc cessful treatment of a variety of human malignancies. Therefore, under standing the molecular mechanisms that underlie cisplatin resistance c ould significantly improve the clinical efficacy of this cytotoxic age nt. Various studies have described that cellular sensitivity to cispla tin can be influenced by several signal transduction pathways. In this review, we examine the role of the cyclic AMP-dependent protein kinas e (PKA) in the modulation of drug resistance in cancer. By a somatic m utant genetic approach, the role of PKA in the development of resistan ce to chemotherapeutic agents has been investigated. A series of mutan ts with decreased PKA activity was examined for their sensitivity to c isplatin. PKA mutants with defective regulatory (RI alpha) subunits, b ut not altered catalytic (C) subunits, exhibit increased resistance to cisplatin, as well as other DNA damaging agents. Furthermore, since R I alpha subunit mutants show enhanced DNA repair we, therefore, hypoth esize that functional inactivation of PKA may result in increased reco gnition and repair of cisplatin lesions. Alternatively, it seems likel y that mutation of the RI alpha subunit may affect cellular sensitivit y to various anticancer drugs, suggesting that the RI alpha subunit ma y have other physiological functions in addition to inhibiting the kin ase activity of the C subunit. Therefore, exploitation of cyclic AMP l evels or functional alteration of the R subunit may potentiate the cyt otoxicity of chemotherapeutic agents and circumvent drug resistance in cancer. More importantly, the altered pattern and mechanism of drug r esistance may offer the opportunity to investigate novel regulatory fu nctions of the RI alpha subunit of PKA. (C) 1998 Elsevier Science Inc.