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.
Highlights
Pancreatic cancer is the most deadly human cancer type [1]
Failure of Smoothened inhibitors in clinical trials in patients with metastasis further confirms that inhibition of canonical Hh signaling alone is not sufficient to reduce pancreatic cancer progression, and indicates that paracrine Shh signaling has a very different role from Hh signaling in the cancer cells
These results suggest that combination of a smoothened inhibitor with a Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase (MEK) inhibitor may be effective in clinical management of metastatic pancreatic cancer
Summary
Pancreatic cancer is the most deadly human cancer type [1]. Pancreatic cancer, the third leading cause of cancer-related death, is predicted to become the second cause of cancer-related death by 2030 in the US (with lung cancer still the number one cause) [2]. Genetic removal of Shh in pancreas or depletion of fibroblasts promotes pancreatic cancer development and progression in KPC-based mouse model [9,10]. These seemly contradicted results may be explained by the fact that both canonical and non-canonical Hh signaling exist during pancreatic cancer development and progression, and non-canonical Hh signaling is not affected by smoothened inhibitors. Failure of Smoothened inhibitors in clinical trials in patients with metastasis further confirms that inhibition of canonical Hh signaling alone is not sufficient to reduce pancreatic cancer progression, and indicates that paracrine Shh signaling has a very different role from Hh signaling in the cancer cells. There are no reported combined therapeutics with smoothened inhibitor and another targeted therapeutic agent in cancer models, and this possibility may help re-initiate more clinical trials for novel cancer treatment
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