Abstract A49: Biological impact of TIMP-1 relative to KRAS status in lung carcinoma

Abstract

Abstract Comprehensive sequence analysis of common human cancers has identified several genes that promote tumorigenesis. KRAS is a commonly mutated oncogene in lung adenocarcinoma, most frequently harboring mutations in codon 12 or 13. Therapeutically targeting of KRAS with small molecules has proven ineffective due to difficulties in disrupting protein/protein interactions that are inherent in its activation and function. Recent work has established that many cancers may have KRAS addiction and are considered KRAS dependent while others do not require KRAS for survival. Previously we have shown that TIMP-1 plays an important role in cell survival in lung adenocarcinoma cells. We have overexpressed TIMP-1 in H2009, a KRAS dependent cell line, which rendered these cells resistant to Staurosporine induced apoptosis, whereas knocking down TIMP-1 in A549 (a KRAS independent lung carcinoma cell line) had the opposite effect. We also noted that TIMP-1 overexpression in H2009 cells made them more angiogenic and aggressive in in vitro assays. H2009 and A549 cell lines also showed significant differences in migration, spheroid formation as well as invasiveness. Although H441 cell line is known to be KRAS dependent, it was not as invasive as H2009. These cell lines also showed differential expression of Vimentin and E-cadherin. These results prompted us to review available data regarding these cell lines, which not only harbored different mutations in the cancer promoting genes, but also differed at the regulatory level and functioned through activated ERK1/2, NFkB and Akt pathways. Analysis with the R2 program (http://hgserver1.amc.nl/cgi-bin/r2/) identified a significant correlation between TIMP-1 and KRAS in breast cancers and lung cancer . Interestingly, high TIMP1 levels have been shown to cause chemoresistance by virtue of its anti-apoptotic activity and KRAS has generally been undruggable. Our current study compares KRAS dependent and independent cell lines in relation to TIMP-1 expression. Modulating TIMP-1 renders these cells either more sensitive or resistant to apoptosis. Clinically, patients with elevated TIMP-1 expression have been shown to have shorter overall survival. This study helps to further dissect these pathways and provides a better understanding of the impact of these mutations in lung carcinoma. Supported in part by a Georgia Research Alliance Distinguished Cancer Scientist Award. Citation Format: Sampa Ghoshal Gupta, Ammar Kutiyanawalla, Byung Rho Lee, Amyn M. Rojiani, Mumtaz V. Rojiani. Biological impact of TIMP-1 relative to KRAS status in lung carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A49. doi: 10.1158/1557-3125.RASONC14-A49