Human pancreatic cancer stem cells are sensitive to dual inhibition of IGF-IR and ErbB receptors

Abstract

BackgroundPancreatic ductal adenocarcinoma is a particularly challenging malignancy characterized by poor responsiveness to conventional chemotherapy. Although this tumor frequently overexpresses or possesses constitutively activated variants of IGF-IR and EGFR/Her-2, clinical trials using inhibitors of these receptors have failed. ErbB receptors have been proposed as one mechanism involved in the resistance to IGF-IR inhibitors. Therefore, combined treatment with inhibitors of both IGF-IR and ErbB receptors would appear to be a good strategy for overcoming the emergence of resistance.MethodsSensitivity of cells to NVP-AEW541 and lapatinib in single or combination treatment was assessed by MTT or WST-8 assays in a panel of human pancreatic cancer cell lines and cancer stem cells. Tumorspheres enriched in cancer stem cells were obtained from cultures growing in non-adherent cell plates. The effects on cell signalling pathways were analyzed by Western blot.ResultsWe found that combined treatment with the IGF-IR and EGFR/Her-2 inhibitors NVP-AEW541 and lapatinib, respectively, synergistically inhibited pancreatic cancer cell growth. Analysis at molecular level argued in favor of cross-talk between IGF-IR and ErbBs pathways at IRS-1 level and indicated that the synergistic effect is associated with the total abolishment of Akt, Erk and IRS-1 phosphorylation. Moreover, these inhibitors acted synergistically in tumorsphere cultures to eliminate cancer stem cells, in contrast to their resistance to gemcitabine.ConclusionsTaken together, these data indicate that simultaneous blockade of IGF-IR and EGFR/Her-2 using NVP-AEW541 and lapatinib may overcome resistance in pancreatic cancer. Thus, the synergy observed with this combined treatment indicates that it may be possible to maximize patient benefit with the appropriate combination of currently known anticancer agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1249-2) contains supplementary material, which is available to authorized users.

A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel

“…Luciferase-expressing cells CP15-Luc were established by transducing the parental cells CP15 cell line established from CP15 tumors [33, 34] with a recombinant retrovirus pLHCluc following standard procedures and selected in 0.2 mg/ml hygromycin. Human pancreatic ductal epithelial cells (HPDE) were kindly provided by Dr. FX Real (CNIO, Madrid, Spain).…”

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

“…For the analysis of combined drug effects cells were cultured with either 0.045 μM PKC412 or 0.5 nM AC220 and 10 μM Ara-C, following the experimental design described in the Results section, aimed at elucidating the probable role of the order of drug administration of chemotherapeutic efficacy. The Coefficient of Drug Interaction (CDI) was calculated as explained in [50]. …”

Concise Review: Pancreatic Cancer and Bone Marrow-Derived Stem Cells

“…However, others have highlighted that pancreatic cancer stem cells may express other/additional receptors and/or markers on their surface, such as CD133, PANC-1, CXCR4 (the receptor for chemoattractant stromal-derived factor-1 [SDF-1]), and c-Met (the tyrosine kinase receptor for hepatocyte growth factor [HGF]), as well as intracellular molecules like aldehyde dehydrogenase-1. Taken together, these findings suggest that, at different molecular levels, biological factors protect these cells from death induced by chemotherapeutic agents and enable their (almost unlimited) proliferation and survival [3][4][5][6][7][8][9][10][11][12][13][14].…”

“…Although this discovery has not resulted in any specific “anti‐stem cell” therapy, it immediately stimulated researchers' interest to develop and examine the efficiency of multiple substances that interfere with various molecular pathways defining the high aggressiveness and proliferation capacity of these cells. For example, recent analyses of reagents such as quercetin, Delta‐like ligand 4 (DLL4) blocking antibodies, and γ‐secretase inhibitors demonstrated promising results in preclinical studies [12–14]. However, the identification of pancreatic cancer stem cells also provided researchers with novel questions regarding the pathogenesis of this deadly disease.…”