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  3. Simultaneous Inhibition of MEK and Hh Signaling Reduces Pancreatic Cancer Metastasis

Simultaneous Inhibition of MEK and Hh Signaling Reduces Pancreatic Cancer Metastasis

  • Cancers (Basel). 2018 Oct 26;10(11):403. doi: 10.3390/cancers10110403.
Dongsheng Gu 1 2,  Hai Lin 3,  Xiaoli Zhang 4 5,  Qipeng Fan 6 7,  Shaoxiong Chen 8,  Safi Shahda 9 10,  Yunlong Liu 11 12,  Jie Sun 13,  Jingwu Xie 14 15
Affiliations

Affiliations

  • 1 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. donggu@iu.edu.
  • 2 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. donggu@iu.edu.
  • 3 Department of Molecular and Medical Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. linhai@umail.iu.edu.
  • 4 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. zhang86@iu.edu.
  • 5 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. zhang86@iu.edu.
  • 6 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. qifan@iu.edu.
  • 7 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. qifan@iu.edu.
  • 8 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. chen251@iupui.edu.
  • 9 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. shahdas@iu.edu.
  • 10 Division of Medical Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. shahdas@iu.edu.
  • 11 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yunliu@iu.edu.
  • 12 Department of Molecular and Medical Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yunliu@iu.edu.
  • 13 Departments of Medicine and Immunology, Mayo Clinic, Rochester, Minnesota, MN 55905, USA. Sun.Jie@mayo.edu.
  • 14 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. jinxie@iu.edu.
  • 15 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. jinxie@iu.edu.
PMID: 30373214 DOI: 10.3390/cancers10110403
Abstract

Pancreatic Cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal Cancer types, with an estimated 44,330 death in 2018 in the US alone. While targeted therapies and immune checkpoint inhibitors have significantly improved treatment options for patients with lung Cancer and renal cell carcinomas, little progress has been made in pancreatic Cancer, with a dismal 5-year survival rate currently at ~8%. Upon diagnosis, the majority of pancreatic Cancer cases (~80%) are already metastatic. Thus, identifying ways to reduce pancreatic Cancer metastasis is an unmet medical need. Furthermore, pancreatic Cancer is notorious resistant to chemotherapy. While Kirsten RAt Sarcoma virus oncogene (K-Ras) mutation is the major driver for pancreatic Cancer, specific inhibition of Ras signaling has been very challenging, and combination therapy is thought to be promising. In this study, we report that combination of Hedgehog (Hh) and Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase (MEK) signaling inhibitors reduces pancreatic Cancer metastasis in mouse models. In mouse models of pancreatic Cancer metastasis using human pancreatic Cancer cells, we found that Hh target gene Gli1 is up-regulated during pancreatic Cancer metastasis. Specific inhibition of smoothened signaling significantly altered the gene expression profile of the tumor microenvironment but had no significant effects on Cancer metastasis. By combining Hh signaling inhibitor BMS833923 with Ras downstream MEK signaling inhibitor AZD6244, we observed reduced number of metastatic nodules in several mouse models for pancreatic Cancer metastasis. These two inhibitors also decreased cell proliferation significantly and reduced CD45⁺ cells (particularly Ly6G⁺CD11b⁺ cells). We demonstrated that depleting Ly6G⁺ CD11b⁺ cells is sufficient to reduce Cancer cell proliferation and the number of metastatic nodules. In vitro, Ly6G⁺ CD11b⁺ cells can stimulate Cancer cell proliferation, and this effect is sensitive to MEK and Hh inhibition. Our studies may help design novel therapeutic strategies to mitigate pancreatic Cancer metastasis.

Keywords

Ihh; MEK; hedgehog; metastatic niche; pancreatic cancer.

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