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  • Title: The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity.
    Author: Lai SW, Bamodu OA, Tsai WC, Chang YM, Lee WH, Yeh CT, Chao TY.
    Journal: Clin Exp Metastasis; 2018 Oct; 35(7):663-677. PubMed ID: 29987671.
    Abstract:
    The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti-metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDHhigh (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF-κB, alongside stemness markers like Oct4 and Sox2, compared to their ALDHlow/null (ALDH-) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-κB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDHhigh/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti-CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFκB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-κB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the 'difficult-to-treat', 'quick-to-relapse' PDAC patients. Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-κB signaling axis and activation of the cell death signaling pathway.
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