Abstract
The role and therapeutic promise of poly-ADP ribose polymerase (PARP) inhibitors in anticancer chemotherapy are increasingly being explored, particularly in adjuvant or maintenance therapy, considering their low efficacy as monotherapy agents and their potentiating effects on concurrently administered contemporary chemotherapeutics. Against the background of increasing acquired resistance to FGFR1 inhibitors and our previous work, which partially demonstrated the caspase-3/PARP-mediated antitumor and antimetastatic efficacy of PD173074, a selective FGFR1 inhibitor, against ALDH-high/FGFR1-rich pancreatic ductal adenocarcinoma (PDAC) cells, we investigated the probable synthetic lethality and therapeutic efficacy of targeted PARP inhibition combined with FGFR1 blockade in patients with PDAC. Using bioinformatics-based analyses of gene expression profiles, co-occurrence and mutual exclusivity, molecular docking, immunofluorescence staining, clonogenicity, Western blotting, cell viability or cytotoxicity screening, and tumorsphere formation assays, we demonstrated that FGFR1 and PARP co-occur, form a complex, and reduce survival in patients with PDAC. Furthermore, FGFR1 and PARP expression was upregulated in FGFR1 inhibitor (dasatinib)-resistant PDAC cell lines SU8686, MiaPaCa2, and PANC-1 compared with that in sensitive cell lines Panc0403, Panc0504, Panc1005, and SUIT-2. Compared with the limited effect of single-agent olaparib (PARP inhibitor) or PD173074 on PANC-1 and SUIT-2 cells, low-dose combination (olaparib + PD173074) treatment significantly, dose-dependently, and synergistically reduced cell viability, upregulated cleaved PARP, pro-caspase (CASP)-9, cleaved-CASP9, and cleaved-CASP3 protein expression, and downregulated Bcl-xL protein expression. Furthermore, combination treatment markedly suppressed the clonogenicity and tumorsphere formation efficiency of PDAC cells regardless of FGFR1 inhibitor-resistance status and enhanced RAD51 and γ-H2AX immunoreactivity. In vivo studies have shown that both early and late initiation of combination therapy markedly suppressed tumor xenograft growth and increase in weight, although the effect was more pronounced in the early initiation group. In conclusion, FGFR1 inhibitor-resistant PDAC cells exhibited sensitivity to PD173074 after olaparib-mediated loss of PARP signaling. The present FGFR1/PARP-mediated synthetic lethality proof-of-concept study provided preclinical evidence of the feasibility and therapeutic efficacy of combinatorial FGFR1/PARP1 inhibition in human PDAC cell lines.
Highlights
Pancreatic cancer is the seventh leading cause of cancer-related deaths globally; it accounts for more than 20% of all deaths caused by abdominal cancers and approximately 5% of all cancer-related deaths [1]
FGFR1-high samples or factor receptor 1 (FGFR1) and PARP1 RNAseq expression profile in six pancreatic ductal adenocarcinoma (PDAC) cell lines that were classified according to their sensitivity to the fibroblast growth factor receptors (FGFRs) inhibitor (FGFRi), dasatinib, for evaluating differential expression
Using immunohistochemical staining, we demonstrated that compared with the phosphate-buffered saline (PBS)-treated control group, tissues from tumors extracted from the BALB/c mice treated with PD173074 and/or olaparib exhibited significantly lower expression of FGFR1, ki-67, and Bcl-2 proteins, with concomitant upregulated cleaved poly-ADP ribose polymerase (PARP) expression (Figure 6G)
Summary
Pancreatic cancer is the seventh leading cause of cancer-related deaths globally; it accounts for more than 20% of all deaths caused by abdominal cancers and approximately 5% of all cancer-related deaths [1]. Subtype, which originates from the pancreatic duct epithelium, represents approximately 85% of the total incidence of pancreatic cancer, and is often unresectable; patients have limited treatment options and exhibit high morbidity and mortality rates [1,2]. A yearly increase was reported in PDAC-specific mortality rates (approximately 98% mortality/incidence), and a consistently low five-year survival rate of
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