Abstract 5482: c-Met and DR5 co-expression is an independent prognostic marker for better survival in colorectal carcinoma

Abstract

Abstract Recently, dysregulated over-expression of hepatocyte growth factor (HGF) and its receptor, c-Met has been reported in variety of cancers. However, its role in colo-rectal carcinoma (CRC) has not been fully elucidated. Therefore, we investigated the role of c-Met in a large series of Middle Eastern CRC patient samples and CRC cell lines. c-Met was over-expressed in 86.8% of CRC and was strongly associated with expression of p-AKT (p<0.0001), DR5 (p=0.0084) and Ki67 (p=0.011) by immuno-histochemistry. Co-expression of c-Met and DR5 was associated with less aggressive phenotype, a better overall survival (p=0.0027) and was an independent prognostic marker. In vitro, PHA665752, a selective c-Met inhibitor, inhibited growth and induced apoptosis in CRC cells. Additionally, PHA665752 treatment caused dephosphorylation of c-Met, AKT and its downstream effector targets FOXO1, GSK-3 and p-Bad. Interestingly, PHA665752 treatment of CRC cell lines also caused up-regulation of DR5 and combination treatment with TRAIL and PHA665752 significantly synergized CRC cells to undergo apoptosis. In-vivo, co-treatment of CRC xenograft with PHA665752 and TRAIL significantly reduced tumor volume and weight. Protein analysis of in-vivo xenografts by immuno-blotting showed that co-treatment with TRAIL and PHA665752 inactivated met and AKT more effectively as compared to treatment with TRAIL or PHA665752 alone. Finally, activation and cleavage of caspase-3 was more pronounced in CRC xenografts treated with combination of TRAIL and PHA665752. Altogether, these data demonstrate a significant correlation between expression of c-Met and DR5 in CRC patients. Furthermore, inhibition of c-Met signaling by PHA665752 in combination with TRAIL significantly inhibited cell growth and induced apoptosis in CRC cell lines suggesting that this may have significant clinical implications as a therapeutic target in the treatment of CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5482. doi:10.1158/1538-7445.AM2011-5482