Concomitant targeting of EGF receptor, TGF-beta and SRC points to a novel therapeutic approach in pancreatic cancer
Authors: Sophie Deharvengt
Melina Marmarelis
Murray Korc
Journal: PloS one (2012)
Discipline: Multidisciplinary
Keywords: EGFR; TGF-β; pancreatic cancer; RNA interference; colony formation
Affiliations: Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, United States of America.

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. 

Retracted: Yes

PubPeer comments:
 Figure 1A: The left (ASPC-1 cells) and right (T3M4 cells) HA-tag panels look very similar, although at slightly different proportions. ![file] , 
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0233436 Following the publication of this article [1], concerns have been raised regarding Figs 1, 4 and S3: The HA-tag panels representing ASPC-1 and T3M4 in Fig 1A appear similar. Figs 1A and 4A: ERK lanes 1u20133 in Fig 1A (ASPC-1) appear similar to the ERK lanes 2u20134 in Fig 4A (ASPC-1) when stretched horizontally. Figs 1A and S3: EGFR lanes 1u20132 in Fig 1A (ASPC-1) appear similar to EGFR lanes 5u20136 in S3 Fig (T3M4) when flipped horizontally. The EGFR lanes 1u20134 (ASPC-1) and the pEGFR lanes 1u20134 (ASPC-1) of Fig 4A appear similar when stretched vertically. Figs 4A and S3: HER2 lanes 1u20134 in Fig 4A (T3M4) appear similar to HER2 lanes 1u20134 (T3M4) in S3 Fig. Figs 4B and S3: ERK lanes 1u20134 in Fig 4B (T3M4) appear similar to ERK lanes 1u20134 (T3M4) in S3 Fig. Original data for the panels of concern are no longer available. Replication data have been provided in support of the results presented in these panels. However, the concerns about western blot data reporting in the original figures remain unresolved. In light of the concerns affecting multiple figure panels that question the integrity of the results, the PLOS ONE Editors retract this article. SD and MM did not respond. MK did not agree with the retraction. Reference 1.Deharvengt S, Marmarelis M, Korc M (2012) Concomitant Targeting of EGF Receptor, TGF-beta and Src Points to a Novel Therapeutic Approach in Pancreatic Cancer. PLoS ONE 7(6): e39684. https: doi.org 10.1371 journal.pone.0039684 ,