Combating pancreatic cancer chemoresistance by triggering multiple cell death pathways

Abstract

Pancreatic cancer is the fourth most common cause of cancer-associated death in western countries, where the incidence and number of deaths are increasing every year. Intrinsic or acquired resistance of tumor cells to chemotherapy agents is the major reason for failure of traditional cancer treatment. Several factors are implicated in this impressive resistance; however, of these, it is important to highlight the extensive cellular heterogeneity of these tumors. This heterogeneity is linked to a wide range of sensitivity that different clones in the same tumor display to chemotherapeutic agents. Accordingly, recent findings in this field have discovered new therapeutic targets in order to develop new combinatory treatments, as well as to induce several cell death pathways and reduce therapy-threshold and likelihood of future resistance. Accordingly, recent research has focused on targeting mitochondria, an organelle with key roles regulating cell death signaling pathways, such as apoptosis, necroptosis, autophagy, ferroptosis, or parthanatos. These findings - identifying new compounds, alone or in combination, that can target pancreatic ductal adenocarcinoma cell resistance - could be the key to future treatments.

Keywords: Apoptosis; Autophagy; Cell death; Chemoresistance; Ferroptosis; Immunogenic cell death; Necroptosis; Pancreas cancer; Parthanatos; Pyroptosis.