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RB Status as a Determinant of Response to UCN-01 in Non-Small Cell Lung Carcinoma¹

Cancer and Molecular Research Laboratory, Division of Hematology/Oncology, Departments of Internal Medicine [P. C. M., D. R. G., P. H. G.] and Medical Biochemistry [J. B. S.], University of California, Davis, Sacramento, California 95817; Northern California Veterans Administration Systems of Clinics, Martinez, California 94553 [D. R. G., M. J. E.]; the Sacramento Medical Foundation Center for Blood Research, Sacramento, California 95816 [T. P.]; and Division of Medical Oncology, Lombardi Cancer Research Center, Georgetown University School of Medicine, Washington DC 20007 [C. B., E. P. G.]

7-Hydroxystaurosporine (UCN-01), a protein kinase inhibitor in clinical development, demonstrates potent antineoplastic activity. To determine whether specific genetic abnormalities would modulate the response to UCN-01, a model of human non-small cell lung carcinoma (NSCLC) cell lines with differential abnormalities of p16^CDKN2, RB, and p53 was used for these studies. Cell growth was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, and cell cycling was studied using flow cytometric analysis of DNA content. Changes in protein levels and phosphorylation were assessed by Western blotting. In cell lines expressing wild-type RB (A549 and Calu1), UCN-01 treatment resulted in dose-dependent growth inhibition, arrest of cells in G₁, and a reduction of cells in S phase. p16^CDKN2-null cells showed similar growth inhibition to normal fetal lung fibroblasts. UCN-01-induced growth arrest was accompanied by induction of p21^CDKN1 and a shift of Rb to the hypophosphorylated state in both p53 wild-type and mutant cell lines. In contrast, UCN-01 treatment of the RB-null cell line H596 resulted in less growth inhibition. To test the role of RB in response to UCN-01, effects of treatment were examined in two human isogenic models of RB expression: the bladder cancer cell line 5637 (RB-null) and the prostate cancer cell line DU-145 (RB-mutant). In the Rb-expressing 5637 subline (RB5), UCN-01 treatment resulted in Rb hypophosphorylation and an accumulation in G₁ in contrast to the parent line. Similarly, the wild-type Rb-expressing DU-145 sublines (DU1.1 and B5) showed increased G₁ arrest compared with the parent cells. We conclude that UCN-01-induced G₁ arrest can occur in cells null for p53 and p16^CDKN2, and that RB status influences the ability of UCN-01 to induce a G₁ arrest. These data suggest that the molecular profile of cell cycle regulating genes in individual tumors may predict responsiveness and provide insight into optimal therapeutic application of this new antineoplastic agent.

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