[1585] Impact on Cell Proliferation of Proteins of the AKT/mTOR and MAPK Pathways in Human Pancreatic Adenocarcinoma

A Handra-Luca, P Hammel, V Rebours, A Sauvanet, A Martin, R Fagard, JF Flejou, J Belghiti, P Bedossa, P Ruszniewski, A Couvelard. APHP Univ Paris 13, Bondy, France; APHP Univ Paris 7, Clichy, France; APHP Univ Paris 13, Bobigny, France; APHP Universite Paris 13, Bobigny, France; APHP Univ Paris 6, Paris, France

Background: The mitogen activated protein kinase (MAPK) and AKT pathways are main signaling pathways involved in cell proliferation, survival and chemoresistance in pancreatic ductal adenocarcinoma (PDAC) carcinogenesis.
Design: We aimed to analyze the expression of the main proteins of the MAPK (ERK1/2, P38, MKK4) and AKT (AKT, mTOR) pathways with respect to cell proliferation in PDAC. The expression of phosphorylated mTOR (p-mTOR), p-AKT, p-ERK1/2, p-P38; of AKT2, MKK4 and of Ki67 was determined by immunohistochemistry in 99 PDAC. Medians of the protein expression score (based on intensity and percentage of stained tumor cells) and of the percentage of Ki67 stained nuclei, were used to classify tumors. Statistical analysis used the Fisher's and Kendall's rank correlation tests.
Results: The expression of the 3 MAPK was coordinated.

	Kendall's Tau	p value	95% Confidence Interval
p-ERK1/2vs.MKK4	0.195	0.0053	-0.0024-0.360
p-ERK1/2vs.p-P38	0.462	<0.0001	0.270-0.6210
MKK4vs.p-P38	0.200	0.0047	-0.0051-0.3900

High expression of the 3 MAPK proteins was related to high p-mTOR [MKK4 (39/60vs.15/45, p<0.0001); p-P38 (23/50vs.8/44, p=0.0047); p-ERK1/2 (28/51vs.15/45, p=0.0411)]. A high cell proliferation Ki67 index was correlated to a high MKK4 (43/57vs.10/37, p<0.0001) and high p-mTOR (41/58vs.10/37, p<0.001), but not to AKT, ERK1/2 or P38.
Conclusions: Our results suggest that in human PDAC: 1) the expression of the 3 MAPK proteins was coordinated and correlated to p-mTOR expression, and that 2) a high cell proliferation was related to high p-mTOR and to MKK4 expression, suggesting a crosstalk between the two signaling pathways, with impact on cell proliferation at p-mTOR level. These data warrant further studies on the framework of these signaling pathways, which could impact on the choice of PDAC treatment.
Category: Liver & Pancreas

Tuesday, March 23, 2010 1:00 PM

Poster Session IV # 212, Tuesday Afternoon