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

Sophie Deharvengt, Melina Marmarelis, Murray Korc

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere39684
JournalPLoS One
Volume7
Issue number6
DOIs
StatePublished - Jun 27 2012

Fingerprint

pancreatic neoplasms
transforming growth factor beta
Pancreatic Neoplasms
Epidermal Growth Factor Receptor
Transforming Growth Factor beta
therapeutics
receptors
Tumors
Neoplasms
cells
Therapeutics
neoplasms
Potassium Iodide
Cell proliferation
RNA Interference
Nude Mice
epidermal growth factor receptors
RNA interference
Cell Proliferation
RNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Concomitant targeting of EGF receptor, TGF-beta and Src points to a novel therapeutic approach in pancreatic cancer. / Deharvengt, Sophie; Marmarelis, Melina; Korc, Murray.

In: PLoS One, Vol. 7, No. 6, e39684, 27.06.2012.

Research output: Contribution to journalArticle

Deharvengt, Sophie ; Marmarelis, Melina ; Korc, Murray. / Concomitant targeting of EGF receptor, TGF-beta and Src points to a novel therapeutic approach in pancreatic cancer. In: PLoS One. 2012 ; Vol. 7, No. 6.
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