[675] Cell Signaling Pathways and KRAS Status in Advanced Colorectal Cancer

S Landolfi, J Hernandez, T Moline, C Romagosa, I de Torres, S Ramon y Cajal. HU Vall Hebron, Barcelona, Spain

Background: Epidermal growth factor receptor (EGFR) and its signaling pathways are known to be altered in colorectal cancer (CRC). The main pathways involved are AKT-mTOR and RAS-RAF-MAPK pathways with their final effectors 4E-BP1 and S6, which regulate mRNA translation. Novel therapeutic agents targeting EGFR have improved outcomes in CRC, althought they are effective only in a subset of patients. KRAS gene mutations (found in 30-40% of CRCs) are associated with poor response to target therapies. On the other hand, the absence of KRAS mutation does not guarantee a better response. Investigation of other genetic/epigenetic biomarkers is necessary to refine the responder population. The aim of this work is to study the role of the factors involved in these pathways and their cross-talk in patients with wild-type (WT) or mutated KRAS, in order to describe their different oncogenic activities.
Design: Fifty metastatic CRCs were selected and KRAS status was determined by real-time PCR. Immunohistochemistry (IHC) was performed for EGFR, Ki-67, p-EGFR, p-MAPK, p-AKT, p-mTOR, p-4E-BP1 and p-S6.
Results: KRAS mutation was found in 40% of the cases. Patients with WT KRAS showed a significant high expression of p-EGFR (p=0.003) and low expression of p-MAPK (p=0.009), compared with mutated KRAS tumors. The study of the cross-talk between the different markers highlighted, in both mutated and WT KRAS tumors, a significant association between p-EGFR levels and p-mTOR levels (p<0.05 in WT KRAS tumors and p<0.01 in mutated KRAS tumors). Additionally, in both groups, the expression levels of p-AKT and Ki-67 correlated (p<0.05 in WT KRAS tumors and p<0.01 in mutated KRAS tumors). Moreover, p-mTOR expression related to p-S6 in both groups (p=0.05). On the other hand, in WT KRAS tumors p-MAPK levels correlated with p-mTOR and p-4E-BP1 (p<0.01), but not with p-S6, while in mutated KRAS tumors there was a correlation between p-S6 and p-MAPK (p<0.01).
Conclusions: In this study we have looked at some of the main up/downstream factors that are involved in the activation of KRAS pathways in CRC, in order to describe the different oncogenic activities of the molecules. p-MAPK was up-regulated in mutated KRAS tumors indicating its role in promoting cell cycle regulation. On the other hand, WT KRAS tumors showed activation of p-EGFR and the AKT – mTOR – 4E-BP1 pathway. These results may suggest that deregulations along this signaling pathway, including others as yet unknown genetic alterations, could be the cause of anti-EGFR target therapy resistance in WT KRAS patients.
Category: Gastrointestinal

Tuesday, March 23, 2010 9:30 AM

Poster Session III # 123, Tuesday Morning

 

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