Metabolic and molecular regulators of therapy resistance in pancreatic cancer

2024 | Vol-1 | Issue-1 | Date of Submission: | Date of Publication:

Abstract

According to the American Cancer Society, pancreatic cancer accounts for about 3% of cancer cases and 7% of cancer-related deaths. Pancreatic ductal adenocarcinoma (PDAC) represents about 95% of pancreatic cancer and is the leading cause of cancer-related death with a dismal mortality rate. The high lethality in pancreatic cancer is partly due to the acquired therapeutic resistance of pancreatic tumors toward most chemotherapeutic agents. Pancreatic tumors exhibit a wide range of metabolic and physiological adaptations, including altered reactive oxygen species (ROS) homeostasis, which plays a significant role in the therapeutic response of chemotherapies. We have developed an in vitro acquired chemotherapeutic resistance cell model by serial exposure of FOLFIRINOX components (5-Fluorouracil, Irinotecan, Oxaliplatin) to pancreatic cancer cell lines. We observed that therapy resistance cell lines exhibit reduced levels of ROS, and exposure of chemotherapeutic agents to these cells results in differential response to ROS alterations. We also observed an altered bioenergetic profile of therapy-resistant cells compared to wild-type cells. Further, we observed increased BACH1 expression in resistant cell lines compared to wild-type cells. BACH1 is a crucial transcription factor, a member of the Cap'n'Collar type of basic region leucine zipper transcription factor family, and plays a very important role in ROS regulation in different types of cells. Our results demonstrate that pharmacological or genetic targeting of BACH1 leads to improved sensitivity of pancreatic cancer cells toward the chemotherapeutic agents. Overall, our results demonstrate that altered ROS homeostasis in pancreatic cancer cells leads to poor sensitivity toward chemotherapeutic agents, and targeting key ROS regulator BACH1 can overcome therapeutic resistance.