Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals.

Cancer Res. 2013 Apr 1;73(7):2221-34.

Miyabayashi K, Ijichi H, Mohri D, Tada M, Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K, Nakai Y, Isayama H, Morishita Y, Omata M, Moses HL, Koike K.

Department of Gastroetnterology, Graduate School of Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.


Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. Although many regimens have been used for PDAC treatment, the combination of the EGF receptor (EGFR) inhibitor erlotinib with gemcitabine has been the only molecular-targeted drug tested so far that has been superior to gemcitabine alone. The mechanism underlying this effective combinational regimen remains unknown. Here, we show that the combination is superior to gemcitabine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout). We found that gemcitabine induced mitogen-activated protein kinase signaling, which was dramatically inhibited by erlotinib even in the Kras-activated PDAC cells in the mouse model. Mechanistic investigations suggested that gemcitabine induces EGFR ligand expression and ERBB2 activation by increasing heterodimer formation with EGFR, thereby maintaining high levels of ERBB2 protein in PDAC cells. Overall, our findings suggest a significant role of ERBB in PDAC treatment. ©2013 AACR.

PMID: 23378339


Supplementary Figure:

(A)EGFR-MAPK signaling without gemcitabine. It is already activated by mutant Kras (Ras).
(B)Gemcitabine (GEM) further activates EGFR-MAPK signaling, by increasing EGFR ligands expression, ERBB2 protein expression and EGFR-ERBB2 heterodimer formation. The increase of EGFR ligands is dependent on MAPK activation.
(C)EGFR inhibitor erlotinib inhibited the gemcitabine-induced EGFR-MAPK signaling.
(D)MEK inhibitor also inhibited the gemcitabine-induced EGFR ligands expression and MAPK activation.
Hideaki Ijichi-1





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