Pd-0332991, A Selective Cyclin-Dependent-Kinase 4/6 Inhibitor, Upregulates Multiple Genes Promoting Invasion And Metastasis In Pancreatic Ductal Adenocarcinoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Deregulation of the Cyclin D-CDK4/6-Rb-E2F signaling pathway is among the most commonly found aberrations in human pancreatic ductal adenocarcinoma (PDAC). PD-0332991 is an orally available, highly specific and reversible inhibitor for Cdk4 and Cdk6, and demonstrates in vitro and in vivo growth inhibitory effects in multiple tumor types. However, the potential usefulness of PD-0332991 in PDAC is currently unknown. In this study, we examined the effects of PD-0332991 on multiple human pancreatic cancer cell lines, and we found that this agent inhibited Rb phosphorylation and E2F target gene expression, and induced G0/G1 cell cycle arrest. However, the growth inhibitory effect was only transient, due to the rapidly emerging compensatory changes of the G1/S machinery components, including upregulation of CyclinD1, Cdk4, and Cdk6, and downregulation of Rb, p107, and p130. Microarray analysis revealed that incubation with PD-0332991 upregulated multiple genes which promote pancreatic cancer invasion, metastasis, angiogenesis, and chemoresistance, including LAMC2, CYR61, SERPINE1, F3, ABCA1, ASNS, and DUSP1. In addition, using matrigel-coated transwell invasion chambers, we demonstrated that incubation with PD-0332991 enhanced the invasiveness of human pancreatic cancer cells. These observations suggest that PD-0332991 may have the potential to cause deleterious effects in PDAC by modulating gene expression in a manner that could promote cancer spread, metastasis, and chemoresistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3055. doi:1538-7445.AM2012-3055