Mechanisms of synergistic action between olaparib and KPT-330 in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and prognostically poor cancer driven by multifaceted mechanisms, notably immune evasion and drug resistance. The majority of PDAC patients present with unresectable locally advanced or metastatic disease, emphasizing a critical unmet need for effective therapies against advanced-stage pancreatic cancer. Despite the proven efficacy of the PARP inhibitor Olaparib against pancreatic cancer in patients carrying BRCA mutations, its practical use is limited by the development of acquired resistance. The clinical application of the PARP inhibitor Olaparib is limited by acquired resistance, making combination therapy a promising strategy to improve treatment responses. Exportin 1 (XPO1) is frequently overexpressed in PDAC cells, representing a therapeutic target, and its inhibitor KPT-330 has demonstrated antitumour potential. Therefore, we aim to combine Olaparib with KPT-330 to enhance its therapeutic effect against PDAC. This study aimed to investigate the synergistic antitumour effects of the combination of Olaparib and KPT-330 against PDAC and to elucidate the underlying molecular mechanisms. We applied RNA sequencing to pancreatic cancer cell lines following combination therapy to identify differentially expressed genes. Separately, Western blotting was performed to measure both the expression and phosphorylation status of key proteins within the involved signaling cascades. The combination of KPT-330 and Olaparib significantly suppressed PDAC cell viability and tumour growth. Mechanistic investigation revealed that the combination specifically reduced SGPP2 levels, leading to inhibition of the IL-6/JAK2/STAT3 signaling axis. Evidence included diminished p-JAK2 and p-STAT3, with no alteration in total JAK2 or STAT3. This SGPP2-associated synergistic effect may overcome olaparib resistance by modulating the immunosuppressive tumor microenvironment. This study reveals that the combination of Olaparib and KPT-330 enhances antitumor efficacy in pancreatic cancer by downregulating SGPP2, a tumor-associated protein, thereby inhibiting the IL-6/JAK2/STAT3 signaling pathway. SGPP2 is proposed as a key molecular node linking the two agents. Collectively, these findings provide preclinical evidence that the Olaparib and KPT-330 combination acts synergistically via the SGPP2/STAT3 axis, supporting its potential application in pancreatic cancer combination therapy.