Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a 5 year survival rate of less than 5%. Deaths caused by pancreatic cancer are projected to exceed the number from colorectal carcinoma by 2020, making PDAC the second leading cause of cancer-related death in the United States, behind only NSCLC. At the molecular level, PDAC is enriched for a number of genetic events central to CDK4/6:CyclinD1 control of cell cycle progression - 90% of tumors harbor oncogenic KRAS mutations, which are synthetic lethal with CDK4/6 inhibition, while the majority of PDAC cases also feature loss of p16INK4A, the endogenous inhibitor of CDK4/6. Rb loss is uncommon in PDAC and phosphorylation of Rb, the canonical CDK4/6 substrate, is detectable at high frequencies, suggesting that aberrant CDK4/6 signaling may be central to loss of cell cycle control in pancreatic cancer.
To determine the significance of CDK4/6 activity in pancreatic cancer, patient-derived xenograft models of early and late stage disease were used to evaluate the selective CDK4/6 inhibitor, palbociclib. Combinatorial efficacy of palbociclib with the standard of care agents, Gemcitabine and nab-paclitaxel (Gem/nab-Pac) was also assessed. The majority of models display greater than 50% tumor growth inhibition following treatment with single agent palbociclib, which is comparable to the response to Gem/nab-Pac in those models. Addition of palbociclib to Gem/nab-Pac confers further benefit in most models by increasing the degree of tumor response on therapy and/or maintaining tumor response after drug removal. To dissect the driver activities in the triplet combination, palbociclib was assessed in combination with either Gem or nab-Pac in a series of tumor growth inhibition/delay studies. Palbociclib and nab-Pac are the dominant agents in the combination - palbociclib/nab-Pac doublet activity surpasses the anti-tumor effects of Gem/nab-Pac in the majority of models, while palbociclib/nab-Pac is equivalent or superior to the triple combination in all models. In contrast, the addition of palbociclib to Gem yields little signs of positive combinatorial activity. Based on these data, the palbociclib/nab-Pac combination will be evaluated in an upcoming clinical trial for PDAC patients. Ongoing pre-clinical studies are focused on the mechanistic and molecular basis for the robust activity of the palbociclib/nab-Pac combination in pancreatic cancer.
Citation Format: Manuel Hidalgo, Camino Menendez, Jing Yuan, Beatriz Salvador, Tao Xie, John Chionis, Pedro Lopez-Casas, Xianxian Zheng, James Hardwick, Paul Rejto, Peter Olson, Todd VanArsdale, David J. Shields. Palbociclib potentiates nab-paclitaxel efficacy in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A42.