Concomitant targeting of EGF receptor, TGF-beta and SRC points to a novel therapeutic approach in pancreatic cancer

• Published in: PloS one 2012-06, Vol.7 (6), p.e39684-e39684
• Main Authors: Deharvengt, Sophie, Marmarelis, Melina, Korc, Murray
• Format: Article
• Language: English
• Subjects: Apoptosis; Biology; Breast cancer; Cancer; Cell culture; Cell proliferation; Colonies; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - drug effects; ErbB Receptors - genetics; ErbB-2 protein; Evolution & development; Gene Knockdown Techniques; Gene Silencing; Genes, erbB-2; Genomes; Growth factors; Health aspects; Humans; In vivo methods and tests; Inhibition; Kinases; Ligands; Medicine; Metastasis; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Phosphorylation; Proto-Oncogene Proteins pp60(c-src) - drug effects; Ribonucleic acid; RNA; RNA-mediated interference; Rodents; Signal monitoring; Signal Transduction; Signaling; Transforming Growth Factor beta - drug effects; Transforming growth factor-b; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039684

To test the hypothesis that concomitant targeting of the epidermal growth factor receptor (EGFR) and transforming growth factor-beta (TGF-β) may offer a novel therapeutic approach in pancreatic cancer, EGFR silencing by RNA interference (shEGFR) was combined with TGF-β sequestration by soluble TGF-β receptor II (sTβRII). Effects on colony formation in 3-dimensional culture, tumor formation in nude mice, and downstream signaling were monitored. In both ASPC-1 and T3M4 cells, either shEGFR or sTβRII significantly inhibited colony formation. However, in ASPC-1 cells, combining shEGFR with sTβRII reduced colony formation more efficiently than either approach alone, whereas in T3M4 cells, shEGFR-mediated inhibition of colony formation was reversed by sTβRII. Similarly, in vivo growth of ASPC-1-derived tumors was attenuated by either shEGFR or sTβRII, and was markedly suppressed by both vectors. By contrast, T3M4-derived tumors either failed to form or were very small when EGFR alone was silenced, and these effects were reversed by sTβRII due to increased cancer cell proliferation. The combination of shEGFR and sTβRII decreased phospho-HER2, phospho-HER3, phoshpo-ERK and phospho-src (Tyr416) levels in ASPC-1 cells but increased their levels in T3M4 cells. Moreover, inhibition of both EGFR and HER2 by lapatinib or of src by SSKI-606, PP2, or dasatinib, blocked the sTβRII-mediated antagonism of colony formation in T3M4 cells. Together, these observations suggest that concomitantly targeting EGFR, TGF-β, and src may constitute a novel therapeutic approach in PDAC that prevents deleterious cross-talk between EGFR family members and TGF-β-dependent pathways.