Abstract
Rapid appearance of resistance to fibroblast growth factor receptor (FGFR) inhibitors hampers targeted regimens in bladder cancer. In the present study, we evaluated whether SIP-SII, a sulphated derivative of the polysaccharide in Sepiella maindroni (spineless cuttlefish) ink used in traditional Chinese medicine, could attenuate resistance to FGFR inhibition in bladder cancer cells. In vitro assays indicated that SIP-SII reduced cell viability and migration, restricted cell cycle progression, and increased apoptosis in parallel with decreased AKT phosphorylation and downregulation of CDK4, MMP2, and Bcl-2 in RT112 and JMSU1 cells. Synergistic effects on cell viability were observed when SIP-SII was combined with the small-molecule FGFR inhibitor AZD4547. Specific Akt targeting by SIP-SII was suggested by the fact that neither Akt knockdown nor the selective PI3K inhibitor BKM120 enhanced the inhibitory effects of SIP-II, while expression of a constitutively active Akt mutant rescued SIP-SII effects. Furthermore, subcutaneous transplantation of RT112 xenografts confirmed the superiority and tolerability of combined SIP-SII and AZD4547 administration over monotherapy regimens. The present study thus provides pre-clinical evidence of the ability of SIP-SII to improve FGFR-targeted therapies for bladder cancer by inhibiting Akt.
Highlights
Bladder cancer is one of the most common cancers worldwide with an estimated 549,393 new cases and 199,922 deaths reported yearly [1]
Our study suggests a potential novel strategy to overcome such resistance by showing that sulfated polysaccharide of Sepiella maindroni ink (SIP-SII), a chemically sulfated polysaccharide isolated from the ink of the cuttlefish Sepiella maindroni, inhibits Akt activation and sensitizes bladder cancer cells to the anti-tumor actions of the fibroblast growth factor receptor (FGFR) inhibitor AZD4547
Among the most relevant signaling pathways investigated in animal models of bladder cancer are the epidermal growth factor receptor (EGFR)-RAS type GTPase family (RAS)-mitogen-activated protein kinase (MAPK) [18], FGFR3RAS-MAPK [19], VEGF-RAS-MAPK [20], PI3K-AktmTOR [21, 22], AR-PI3K/Akt [23], and STAT3Survivin [24] pathways
Summary
Bladder cancer is one of the most common cancers worldwide with an estimated 549,393 new cases and 199,922 deaths reported yearly [1]. In recent years multiple signaling pathways involved in bladder cancer progression have been identified as druggable targets. These include the PI3K/Akt/mTOR pathway, the RTK/RAS/MAPK pathway, and the JAK/STAT pathway [2]. The first targeted therapy for metastatic bladder cancer, the panFGFR inhibitor erdafitinib, has recently received FDA approval. A common issue with targeted therapies is intrinsic or acquired resistance of cancer cells. AKT hyperactivation, MET overexpression, BRAF fusion, and activation of canonical MAPK-ERK signaling have been implicated in resistance to FGFR inhibitors [6,7,8,9]. Discovery and evaluation of potential compounds that can reverse FGFR inhibitor resistance is critical for improving targeted regimens
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