In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 851-851
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers. New therapeutic approaches to improve the prognosis are highly required. We generated pancreas-specific TGF-beta receptor II (Tgfbr2) knockout mice in the context of Kras activation, which recapitulated clinical and histopathological manifestations of human PDAC, indicating that an impact of blockade of TGF-beta signaling in PDAC progression. An EGFR inhibitor erlotinib showed a superior survival effect in combination with gemictabine, however, the mechanism by which PDAC with extremely frequent KRAS-mutation benefits from EGFR inhibition remains largely unkown. Using the model we investigated the anti-tumor impact and mechanisms of erlotinib in combination with gemcitabine. We treated the mice with elrotinib and gemcitabine. Median survival times were 52.5, 69, and 74 days for control, gemcitabine alone, and gemcitabine + erlotinib, respectively. Gemcitabine alone significantly extended the survival compared to the control. Further, adding erlotinib to gemcitabine prolonged the survival significantly compared to gemcitabine alone. Interestingly, treatment with gemcitabine enhanced the activation of MAPK signaling, which was inhibited by adding erlotinib, even in the KRAS-mutant PDAC in vivo and in vitro. We observed that the gemcitabine-induced MAPK signaling activation was due to induction of EGFR ligands expression and also due to ERBB2 activation in PDAC cells. Erlotinib inhibited the ERBB2 activation, partly by inhibiting heterodimer formation with EGFR and also decreasing ERBB2 protein expression in PDAC cells. This mouse model appears recapitulating chemosensitivity of human PDAC and indicates the significance of ERBBs in PDAC treatment. This model also might provide important insights into the beneficial patient subpopulation and the mechanism of the action of drugs and chemoresistance, in which TGF-beta signaling might be highly involved. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 851. doi:1538-7445.AM2012-851
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-851
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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