CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target

Simple Summary Pancreatic cancer is a challenging disease to treat effectively. Fibroblasts associated with pancreatic cancer contribute to disease progression by secreting factors that enhance tumor cell survival and help tumor cells avoid detection by the immune system. This overview focuses on a chemokine, CXCL12, produced by cancer-associated fibroblasts and how CXCL12 signaling enhances pancreatic cancer progression by contributing to various hallmarks of cancer including, but not limited to, tumor growth and evasion of immune response. These pro-oncogenic functions of CXCL12 make it an attractive target in pancreatic cancer. We discuss the different approaches in development to therapeutically target CXCL12 and finally propose a novel approach, the use of the farnesyl transferase inhibitor tipifarnib to inhibit CXCL12 expression in pancreatic fibroblasts. Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion. In this review, we focus on one such chemokine, CXCL12, secreted by the cancer-associated fibroblasts and discuss its contribution to several of the classical hallmarks of PDAC and other tumors. We review the various therapeutic approaches in development to target CXCL12 signaling in PDAC. Finally, we propose an unconventional use of tipifarnib, a farnesyl transferase inhibitor, to inhibit CXCL12 production in PDAC.

Automated summary

Pancreatic cancer is a challenging disease with limited therapeutic options and poor long-term survival. This review focuses on the role of a chemokine called CXCL12, secreted by cancer-associated fibroblasts, in promoting various hallmarks of pancreatic cancer such as tumor growth and evasion of immune response. Different approaches to target CXCL12 signaling are discussed, and a novel approach using a farnesyl transferase inhibitor called tipifarnib to inhibit CXCL12 production in pancreatic fibroblasts is proposed.