Abstract 5594: JNK1 and MERTK are markers of MEK inhibitor resistance and new targets for therapy.

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating human cancers, having a median survival of 6 months and a 5-year survival rate of 6%. It is the fourth leading cause of cancer deaths due to its resistance to conventional radiotherapy and chemotherapy and a lack of early detection. Alternatively, small molecule inhibitors have been emerging as a means of transitioning away from non-selective treatments towards a more personalized approach. Pancreatic cancer, having mutant K-RAS and TP53 in upwards of 90% of cases, appears to be a great candidate for molecular therapy due to this high genetic homogeneity among patients. TP53 is an inactivation mutation and not a candidate for inhibition. K-RAS is an over-activating mutation but unfortunately cannot currently be treated by small molecule inhibitors. However, its downstream pathways, which signal both growth and survival, can. The most predominant of these is the MAP kinase pathway. Several small molecules have been developed to target members of this pathway such as MEK 1/2 including U0126, PD0325901 and AZD6244. Often, however, these therapies are still ineffective and it would be immensely beneficial to be able to predict when MEK inhibition will be effective or should conversely be avoided. To discover such markers, we tested a panel of 18 pancreatic cancer cell lines for sensitivity to the MEK inhibitor AZD6244. After classifying each line's sensitivity, microarray and qPCR analysis found significantly different genes between the sensitive and resistant groups. Most notable were MERTK and MAPK8, which both were upregulated in resistant lines and showed some redundancy in the studies. These genes code for the Tyrosine-protein kinase Mer (MERTK) and c-Jun N-terminal kinase (JNK1) proteins respectively. Correlation studies showed both gene and protein expression levels to track with resistance to the small molecule inhibitor. To test whether these genes and the proteins they code for could serve as potential new therapy targets, shRNA studies were performed. Studies yielded a noticeable decrease in proliferation in both MAPK8 and MERTK knockdown, even being lethal in one case. While the results support the importance of these proteins for tumorgenecity, knockdown did not alter the cell lines’ sensitivity to MEK inhibition. Our findings suggest the use of MERTK and JNK1 as markers of MEK inhibition resistance and propose new target for future therapies. Citation Format: Jaymes Beech, Kim Kelly. JNK1 and MERTK are markers of MEK inhibitor resistance and new targets for therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5594. doi:10.1158/1538-7445.AM2013-5594