Clinical utility of PET/CT and diagnostic laparoscopy in pancreatic cancer staging

Abstract

dissemination and therapy resistance in PADC via activation of down-stream pathways such as PI3K/AKT and Ras/Raf/MAPK. This family is overexpressed in 42-90% of PDAC, which associates with disease progression and poor overall survival. Despite the key roles of the ErbB family in initiation and malignant progression of PDAC, clinical trials with ErbB-targeting agents such as erlotinib, gefitinib, cetuximab, trastuzumab and lapatinib have been disappointing. In this preclinical study, we investigated the anti-tumor activities of dacomitinib, a pan-inhibitor of the ErbB receptors, in PDAC cell lines. Methods: MTT assay was performed to evaluate cell viability. qRT-PCR was conducted to measure the expression levels of FOXM1, c-Myc, AURKB, N-cadherin and TWIST1. Propium iodide staining was performed to analyze cell cycle distribution and Annexin/ PI assay was carried out to evaluate induction of apoptosis. We performed Western blot analysis to measure the expression levels of survivin, Bcl-2, p21, XIAP, Mcl1, cIAP1, cIAP2, FOXM1, cyclin B1, CDC25C, AURKB, CDK1, and EMT markers N-cadherin, Snail, ZEB1 and Twist1. Results: This report showed the advantage of pan-inhibition of the ErbB receptors by dacomitinib, as compared to the single targeted therapy agents including cetuximab, gefitinib, trastuzumab, H3.105.5 (anti-HER3 mAb) and lapatinib. Dacomitinib, but not the other agents, inhibited cell growth and induced apoptosis via reduction of the protein levels of survivin, Bcl-2, XIAP, Mcl1, cIAP1, cIAP2, FOXM1, cyclin B1, CDC25C, AURKB and CDK1. Moreover, dacomitinib decreased the expression of the EMT markers. Conclusions: These finding suggest that blockade of the ErbB receptors has more antitumor efficacy compared to single or dual blocking in this family. Moreover, our results provide a rationale for further investigation on the therapeutic potential of dacomitinib in treatment of the PADC.