Data analysis was performed using Calcusyn software (Biosoft, UK) and interpreted as follow: 0.9=synergistic effect, 0.9C1.1=additive effect, 1.1=antagonistic effect. Western blot analysis The effect of various brokers on downstream signaling molecules of BxPC-3 and Capan-1 cells was investigated using western blot analysis. expression of EGFR and HER2 was high or intermediate in all HPCCLs. Of all the agents examined, the CDK1/2/5/9 inhibitor, dinacicilib, was the most potent agent which inhibited the proliferation of all seven HPCCLs with IC50 values of 10 nM, followed by SRC targeting TKI dasatinib (IC50 of 258 nM), gemcitabine (IC50 of 330 nM), stattic (IC50 of 2 M) and the irreversible pan-HER TKI afatinib (IC50 of 2.95 M). Treatment with afatinib and dasatinib inhibited the ligand-induced phosphorylation of EGFR and SRC respectively. Statistically significant associations were AMG 837 calcium hydrate found between HER2 expression and response to treatment with the ALK/IGF-IR/InsR inhibitor ceritinib and fibroblast growth factor receptor (FGFR)1/2/3 inhibitor AZD4547, HER3 and IGF-IR expression and their response to treatment with TKIs targeting HER family members (erlotinib and afatinib), AMG 837 calcium hydrate and c-MET and ALK7 expression and their response to treatment with stattic. Interestingly, treatment with a combination of afatinib with dasatinib and gemcitabine with dasatinib resulted in synergistic tumor growth inhibition in all HPCCLs examined. In contrast, the combination of afatinib with dinaciclib was found to be antagonistic. Finally, the treatment with afatinib, dasatinib and dinaciclib strongly inhibited the migration of all HPCCLs examined. In conclusion, the CDK1/2/5/9 inhibitor dinaciclib, irreversible pan-HER TKI afatinib and SRC targeting TKI dasatinib were most EPHB2 effective at inhibiting the proliferation and migration of HPCCLs and the combination of afatinib with dasatinib and gemcitabine with dasatinib led to synergistic tumor growth inhibition in all HPCCLs examined. Our results support further investigation on the therapeutic potential of these combinations in future clinical trials in pancreatic malignancy. contamination and non-modifiable factors such as age, sex (male predominance), race/ethnicity (higher incidence in black populace), blood group (A, B and AB), family history and genetic susceptibility (e.g., BRCA2 mutation) have been identified that increase the likelihood of developing pancreatic malignancy (2C6). Despite preventive steps (e.g., avoidance of above risk factors) and numerous improvements in the imaging technologies and the development of malignancy therapeutics in the past few decades, around 80C85% of patients with pancreatic malignancy have an unresectable tumor at the time of presentation with the 5-12 months survival rate of only 9% (2C6). Therefore, there is an urgent need not only to identify biomarkers of diagnostic, AMG 837 calcium hydrate prognostic and predictive value but also to develop more effective and less harmful therapeutic interventions. Growth factor receptor tyrosine kinases (RTKs) with tyrosine kinase activity and AMG 837 calcium hydrate their downstream cell signaling molecules are important not only in normal development but also when aberrantly expressed or activated in the pathogenesis of human cancers and therapeutic targets. One such example is the human epidermal growth factor receptor subfamily (also called EGFR or ErbB family) which consists of four users; ErbB1/HER1/(also called EGFR), ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4 (7). Upon ligand binding (EGF, AR and TGF for EGFR, HB-EGF, BTC, Epiregulin for EGFR/HER4 and NGR1-4 for HER3/4) conformational changes in the extracellular domain name of ErbB receptor are induced resulting in the formation of homodimers or heterodimers between ErbB family members. This prospects to an auto and/or trans-phosphorylation of C-terminal region of the intracellular tyrosine kinase domain name leading to the activation of various downstream signaling pathways such as PI3K-AKT, RAS/RAF/MAPK, JAK-STAT and em PLC /em -1 that regulates proliferation, metabolism, angiogenesis, cell progression and survival (7C9). In some studies, aberrant expression and activation of HER-mediated signaling has been associated with tumor aggressiveness and a poorer prognosis in patients with pancreatic malignancy (7,10C13). However, of the HER inhibitors, only the reversible EGFR-specific erlotinib has been approved by the US FDA for the treatment of locally advanced, unresectable or metastatic pancreatic malignancy when used in combination with gemcitabine (14). While erlotinib.