TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and often lethal malignancy, requiring the development of enhanced therapeutic approaches. The DNA damage response (DDR) pathway is frequently altered during PDAC development, leading to an increased occurrence of DNA damage. DNA topoisomerase II-binding protein 1 (TOPBP1) plays a supportive role in regulating the DDR pathway, and its overexpression has been linked to the tumorigenesis of various cancers. This study investigated the biological role of TOPBP1 in PDAC pathogenesis and evaluated its clinical relevance in guiding treatment regimens. We examined the relationship between TOPBP1 expression, DDR pathway modulation, and therapeutic response in PDAC cell lines, primary cells, and subcutaneous mouse models. We found that elevated TOPBP1 expression was positively correlated with increased histologic grade and reduced patient survival in PDAC. TOPBP1 knockdown increased the sensitivity of PDAC cells to olaparib treatment and improved therapeutic efficacy in both PDAC cell lines and subcutaneous mouse models. Combination treatment with olaparib and AZD6738 effectively induced P53-dependent apoptosis via inhibiting the ATR pathway and enhancing signaling through the ATM pathway, which significantly reduced the viability of pancreatic cell lines. Notably, this combination therapy was more effective in PDAC cell lines exhibiting high TOPBP1 expression, indicating that TOPBP1 may serve as a useful predictive biomarker. In conclusion, TOPBP1 is a potential marker for optimizing the olaparib and AZD6738 combination therapy in PDAC. This study highlights the clinical significance of TOPBP1 in the treatment of PDAC and emphasizes the potential implications for a broader population of patients.