Investigation of the possible synergistic effect of bortezomib and imatinib in pancreatic cancer

The high mortality rate among pancreatic cancer patients underlines the importance of proper treatment. However, the traditional treatment strategies remain inadequate indicating that alternative therapy options need to be explored. Bortezomib is a proteasome inhibitor which blocks the removal of aberrant proteins and causes their accumulation in endoplasmic reticulum (ER) which in turn triggers stress in this organelle. The active protein synthesis in pancreas emphasizes the need for a stringent central of protein homeostasis thus bortezomib might be a good candidate for pancreatic cancer treatment. However, it is important to note that exceeding the stress threshold is crucial, indicating that combination of bortezomib with other ER stress activating drugs might increase the effectiveness of therapy. Imatinib is a tyrosine kinase inhibitor that is used for the purpose of combination with bortezomib due to its known effect on ER stress activation. In this thesis, we aimed to understand if combination of bortezomib and imatinib shows a synergistic effect on pancreatic cancer cells. We showed that both bortezomib and imatinib activates ER stress in BxPC-3 and MIA PaCa-2 pancreatic cancer cells via analysing sXBP1 levels by qRT-PCR. Our findings revealed that the combination of these drugs resulted in a synergistic effect in the cancer cell death. It is also discovered that both imatinib and bortezomib have an activator impact on the RIDD mechanism. In silico analysis further unveiled that ER stress-related genes DERL2, DNAJB11, EDEM1, EIF2AK3, HSPA5, CEBPB may be involved in bortezomib resistance in pancreatic cancers. Overall, our study discovered the previously unknown effects of imatinib and bortezomib in pancreatic cancer cells and indicated that activation of ER stress induced death might be used as a therapy option for pancreatic cancer treatment.