pf-00299804 and Carcinoma--Pancreatic-Ductal

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is the fourth most common cause of cancer-related death in the USA. Local progression, early tumor dissemination and low efficacy of current treatments are the major reasons for its high mortality rate. The ERBB family is over-expressed in PDAC and plays essential roles in its tumorigenesis; however, single-targeted ERBB inhibitors have shown limited activity in this disease. Here, we examined the anti-tumor activity of dacomitinib, a pan-ERBB receptor inhibitor, on PDAC cells.. Anti-proliferative effects of dacomitinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of dacomitinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of dacomitinib.. We found that dacomitinib diminished PDAC cell proliferation via inhibition of FOXM1 and its targets Aurora kinase B and cyclin B1. Moreover, we found that dacomitinib induced apoptosis and potentiated radio-sensitivity via inhibition of the anti-apoptotic proteins survivin and MCL1. Treatment with dacomitinib attenuated cell migration and invasion through inhibition of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, Snail and N-cadherin. In contrast, we found that the anti-tumor activity of single-targeted ERBB agents including cetuximab (anti-EGFR mAb), trastuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small molecule inhibitor) were marginal.. Our findings indicate that dacomitinib-mediated blockade of the ERBB receptors yields advantages over single-targeted ERBB inhibition and provide a rationale for further investigation of the therapeutic potential of dacomitinib in the treatment of ERBB-driven PDAC.

Topics: Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; ErbB Receptors; Humans; Models, Biological; Neoplasm Invasiveness; Pancreatic Neoplasms; Quinazolinones; Radiation Tolerance