Abstract 5221: MAP3K11 regulates hedgehog signaling and suppresses tumor microenvironment in genetic mouse models of pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 5%. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for PDA patients to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is characteristic of PDA. Therefore, it is extremely important to identify alternative pathways which can be targeted in PDA. Here we report a MLK-mediated novel pathway that promotes oncogenic potential of Gli1, an effector of hedgehog pathway (Hh), can be inhibited in PDA. Earlier, we reported that MLK3 phosphorylates Pin1 on Ser138 site and increases its catalytic activity and nuclear translocation. In order to identify targets of MLK3 and nuclear p-Pin1, we performed cancer specific gene expression profiling and found 13-fold up-regulation of Gli1 transcript, suggesting MLK3-Pin1-Gli1 axis could activate Hh pathway. Most importantly, MLK3, pMLK3, Pin1 and Gli1 were overexpressed in human pancreatic cancer tissues, compared to normal adjacent tissues. Interestingly, MLK3 was able to directly phosphorylate Gli1 on specific residues and the transcriptional activity of Gli1 was synergistically regulated by Pin1 and MLK3 together, which was partially blocked by pan-MLK inhibitor, CEP-1347. Another key finding was that CEP-1347 reduced the expression of Kras-G12D in the pancreatic cell lines derived from KPC mice. Therefore, we expanded our studies to demonstrate the therapeutic effects of MLK inhibition by CEP-1347 in genetically engineered mouse models of pancreatic cancer. LSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was used to investigate this effect in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; Pdx1-Cre (KPC) mouse model was used to evaluate this in PDAC. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and PanIN lesions in KC and KPC mice with an increased cytokeratin 19 (CK19)-stained area. CEP treatment diminished chronic pancreatitis-mediated ADM and PanIN formation. In addition, it alleviated the percent area of Masson's trichrome staining, α-SMA and vimentin expression. In KPC mice, CEP-1347 inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival. In conclusion, our findings suggest that pathological activation of MLK3-Pin1 axis could promote survival of pancreatic cancer cells via Hh pathway activation. Collectively our results suggest that targeting MLKs could be an alternative approach to overcome Desmoplasia and PDAC. Citation Format: Navin Viswakarma, Gautam Sondarva, Lucas Ibrahimi, Daniel R. Principe, Basabi Rana, Ajay Rana. MAP3K11 regulates hedgehog signaling and suppresses tumor microenvironment in genetic mouse models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5221.