The frequent mutational activation of KRAS in pancreatic ductal adenocarcinoma (PDAC) (greater than 90%) and critical importance of K-Ras-driven signaling in PDAC progression has led to increased efforts to identify K-Ras-targeted therapies. Activation of RalA downstream of K-Ras is essential for anchorage-independent and in vivo growth of PDAC cell lines. Indeed RalA-GTP levels are significantly higher in patient tumors relative to normal matched and unmatched samples. Phosphorylation of RalA on S194 by Aurora A kinase is critical for RalA-mediated effects on PDAC tumorigenesis. In addition S194 RalA phosphorylation is increased in PDAC cell lines relative to immortalized nestin-positive pancreatic epithelial cells. This evidence suggests that targeting RalA phosphorylation with Aurora A kinase inhibitors may prove to be a viable therapeutic option for the treatment of pancreatic cancer. MLN8237 is a novel and specific Aurora A kinase inhibitor. Therefore, we investigated the effectiveness of the MLN8237 at inhibiting anchorage-independent growth of PDAC cell lines and human tumorgraft growth in vivo. In addition, we investigated whether RalA phosphorylation could serve as a biomarker for MLN8237 responsiveness. MLN8237 decreased anchorage-independent growth of a panel of PDAC cell lines, some modestly and others dramatically, at nanomolar concentrations. In addition, administration of MLN8237 resulted in tumor regression in a subset of patient-derived tumorgrafts. Decreases in RalA phosphorylation were observed upon administration of MLN8237 but did not correlate with responsiveness in cell lines or tumorgrafts. These data suggest that further investigation of MLN8237 in a subset of PDAC patients is warranted, though non-clinical data suggests that activity may be RalA-independent. Furthermore, RalA phosphorylation does not appear to be a predictive biomarker for responsiveness to MLN8237.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C188.