Investigation of Anti-Tumor Effects of an MLK1 Inhibitor in Prostate and Pancreatic Cancers

SIMPLE SUMMARY: Both prostate and pancreatic cancers are ranked in the top five leading causes of cancer death in American. In prostate cancer, the mainstay of therapeutic approaches is inhibition of the androgen receptor; however, resistance occurs within two years. In pancreatic cancer, there is no targeted therapy available, and patients have the worst survival rate compared to all other types of cancer. We identified a novel MLK1 inhibitor (NSC14465) and demonstrated anti-tumor ability in both prostate and pancreatic cancers. ABSTRACT: It was shown that mixed lineage kinase 1 (MLK1) regulates pancreatic cancer growth; however, its role in prostate cancer remains unclear. We showed that MLK1 is a tumor marker in prostate cancer by analyzing clinical gene expression data and identified a novel MLK1 inhibitor (NSC14465) from the compound library of the National Cancer Institute (NCI) using a MLK1 protein structure. The inhibitory effects of MLK1 were validated by an in vitro kinase assay and by monitoring phosphorylation signaling, and the anti-proliferation function was shown in several prostate and pancreatic cancer cell lines. We also demonstrated anti-tumor ability and prevention of cancer-related weight loss in a syngeneic orthotopic mouse model of pancreatic cancer that mimicked the tumor growth environment in the pancreas. Our results demonstrate that the MLK1 inhibitor is an anti-tumor agent for malignant prostate and pancreatic cancers.