Cancer Biology and Signal Transduction Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

The high prevalence of KRAS mutations and importance of the RalGEF–Ral pathway downstream of activated K-ras in pancreatic ductal adenocarcinoma (PDAC) emphasize the importance of identifying novel methods bywhich to therapeutically target thesepathways. Itwas recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase (AAK) is critical for PDAC tumorigenesis. We sought to evaluate the AAKselective inhibitor MLN8237 as a potential indirect anti-RalA–targeted therapy for PDAC. We used a sitespecificphospho-S194RalAantibodyanddetermined thatRalAS194phosphorylation levelswere elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate thatMLN8237 treatmentmaybe effective for a subset ofpatientswithPDAC independent ofRalAS194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment. Mol Cancer Ther; 13(1); 122–33. 2013 AACR.