Combination of gemcitabine and erlotinib inhibits recurrent pancreatic cancer growth in mice via the JAK-STAT pathway

Abstract

Compared to single gemcitabine treatment, the combination of gemcitabine and erlotinib has shown effective response in patients with locally advanced or metastatic pancreatic cancer. However, the combination therapy has not proven effective in patients with pancreatic cancer after R0 or R1 resection. In the present study, a nude mice model of orthotopic xenotransplantation after tumor resection was established using pancreatic cancer cell lines, BxPC-3 and PANC-1. Mice were divided in four groups (each with n=12) and were treated as follows: the control group received a placebo via intraperitoneal injection (i.p.), while the other three groups were treated with gemcitabine (50 mg/kg i.p., twice a week), erlotinib (50 mg/kg oral gavage, once every three days), and combined treatment of gemcitabine and erlotinib, respectively. The treatment lasted for 21 days, after which all mice were sacrificed and tumors were examined ex vivo. We determined that the combination of gemcitabine and erlotinib inhibited recurrent tumor growth and induced apoptosis in vivo by downregulating phosphorylation levels of JAKs and STATs, which in turn downregulated the downstream proteins HIF-1α and cyclin D1, and upregulated caspase-9 and caspase-3 expression. To sum up, the combination of gemcitabine with erlotinib was effective in treating patients with pancreatic cancer after R0 or R1 resection.

Genome-scale analysis to identify prognostic microRNA biomarkers in patients with early stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy

“… 69 , 70 Similar anti-tumor drugs in PC target the JAK-STAT pathway and may have a potential application in chemotherapy and immunotherapy. 71 , 72 Therefore, we can hypothesize that these prognostic miRNAs are involved in biological processes and signaling pathways by regulating their target genes and affecting PC tumorigenesis and treatment. Regarding the top five significant target genes, the present study is the first to identify a significant association between these mRNA expression levels and PDAC OS.…”

Molecular therapeutic strategies targeting pancreatic cancer induced cachexia

“…While the exact mechanism of this pathway’s cachectic effect is unclear, it is likely due to an increase in pro-inflammatory cytokines, acute phase reactants, and catabolic factors. Intracellular JAK2-STAT3 pathway is activated by weight loss and inflammation associated cytokines IL-6, IL-11, leukaemia inhibitory factor, and TNF-α; thus inhibition is both multi-faceted and approachable[33,40,41]. Multiple studies have demonstrated attenuation of cachexia by inhibiting the JAK2-STAT3 pathway or its downstream signaling colorectal and lung cancer[36-39].…”

A Polymeric Nanogel-Based Treatment Regimen for Enhanced Efficacy and Sequential Administration of Synergistic Drug Combination in Pancreatic Cancer

“…For the last 2 decades, Gem has become the reliable drug regimen for advanced PC, as it has shown significant betterment in the median overall survival of patients in clinical trials (Sinn et al, 2017;Goess and Friess, 2018). Large bodies of research evidence suggest the advantages of using combination therapy of Gem with other cytotoxic agents (Von Hoff et al, 2013;Hamada et al, 2017;Chakraborty et al, 2018;Chen et al, 2018). Although these combination therapies show significant improvement in prolongation of overall median survival in clinical trials, long-term survival of patients remains poor (American Cancer Society, 2017), demanding novel effective therapeutic approaches against disease progression.…”