Abstract B115: PD0332991 induces epithelial to mesenchymal transition in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related death among both men and women in the United States, with an overall survival rate of 6%. Moreover, the median survival in PDAC is only five to six months, underscoring the need for improved therapies. Cancer cell proliferation and cell cycle dysregulation is a major target in cancer treatment. Cyclin-dependent kinase (CDK) and cyclin inhibitors act as anti-proliferative agents that target upregulated cell-cycle progression proteins in various tumors. The efficacy of PD0332991, a CDK4/6 inhibitor, is currently being investigated in clinical trials in patients with retinoblastoma protein (Rb)-positive breast, ovarian, and non-small-cell lung cancers, but has not yet been examined for treatment in PDAC. We have recently shown that PD0332991 inhibits cell proliferation in PDAC cell lines but initiates epithelial to mesenchymal transition (EMT) and induces cancer cell invasion in some of these cells. Using human PDAC tissues and tissues from genetically engineered mouse models (GEMMs) of PDAC, we also recently showed that loss of RB function is common in PDAC. To further assess the therapeutic potential of PD0332991 in PDAC, we now compared its effects in PANC-1 human PDAC cells (wild-type RB1 gene) and in murine PDAC cells devoid of RB that were derived from a GEMM expressing mutant KRAS G12D (KRC mice). In PANC-1 cells, PD0332991 (1 μM) inhibited proliferation and induced EMT. By contrast, in KRC 1022-4 murine PDAC cells, the same concentration of PD0332991 induced EMT without altering proliferation. Moreover, removal of PD0332991 from the incubation medium reversed its growth inhibitory actions in PANC-1 cells, but did not reverse its effects on EMT in either PANC-1 or KRC 1022-4 cells. Taken together, these findings suggest that PD0332991 may exert long-term deleterious effects in patients with PDAC limiting its potential therapeutic use in this deadly cancer, except in conjunction with agents that target EMT. This study was supported, in part, by NCI grant R37-075059 to MK. Citation Format: I. E. Imasuen, A. Jesse Gore, M. Korc. PD0332991 induces epithelial to mesenchymal transition in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B115.