SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

作     者：Ornella Randazzo Stella M.Cascioferro Camilla Pecoraro Widad Ait Iddouch Amir Avan Barbara Parrino Daniela Carbone Ugo Perricone Godefridus J.Peters Patrizia Diana Elisa Giovannetti 

作者机构：Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCVU University Medical CenterAmsterdam 1081 HVThe Netherlands Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche(STEBICEF)Universitàdegli Studi di PalermoPalermo 90133Italy Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashhad 91886-17871Iran Cancer Research CenterMashhad University of Medical SciencesMashhad 91886-17871Iran Student Research CommitteeSchool of MedicineMashhad University of Medical SciencesMashhad 91886-17871Iran Drug Discovery UnitFondazione Ri.MEDPalermo 90128Italy Department of BiochemistryMedical University of GdanskGdansk 80-210Poland Cancer Pharmacology LabAIRC Start Up UnitFondazione Pisana per la ScienzaPisa 56124Italy. 

出 版 物：《Cancer Drug Resistance》 (癌症耐药（英文）)

年 卷 期：2021年第4卷第4期

页      面：904-922页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：This work was supported by Cancer Center Amsterdam(CCA)Foundation grants 2015 and 2018 Italian Association for Cancer Research(AIRC)IG grant to Giovannetti E,European Union 2014-2020 PON Ricerca e Innovazione grant from the Italian Ministry of Education,University and Research,entitled“PROGEMA-Processi Green per l’Estrazione di Principi Attivi e la Depurazione di Matrici di Scarto e Non”(ARS01_00432)to Diana P 

主　　题：Pancreatic ductal adenocarcinoma gemcitabine indole derivatives anti-proliferative activity anti-migratory activity SF3B1 RON hENT1 

摘      要：Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine,one of the standard drugs,in PDAC cell ***:One imidazo[2,1-b][1,3,4]thiadiazole derivative(IS1)and three indole derivatives(IS2,IS3 and IS4),selected by virtual screening from an in-house library,were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2,Hs766t and Panc05.04,the latter harbouring the SF3B1 *** effects on the splicing pattern of proto-oncogene recepteur d’origine nantais(RON)and the gemcitabine transporter human equilibrative nucleoside transporter-1(hENT1)were assessed by PCR,while the ability to reduce tumour volume was tested in spheroids of primary PDAC ***:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell *** compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h ***,IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures,and these results might be explained by the statistically significant increase in hENT1 expression(P0.05 *** control cells),potentially reversing PDAC ***:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.