Pancreatic cancer is the only human malignancy for which patients’ survival has not improved substantially during the past 30
years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic
treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination
with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction
of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the
disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation.
This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic
cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel
agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances
in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging
therapeutic targets to overcome this resistance.
Keywords: Pancreatic cancer, combination therapies, drug resistance, FOLFIRINOX, nab-paclitaxel, TGF-β, hypoxia.
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