title: Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors.
abstract: Choline kinase α (CHKα) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKα in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKα expression, associated with differentiation. CHKα protein expression was directly correlated with sensitivity to MN58b, a CHKα inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKα knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKα inhibition and, in vitro, MN58b had additive or synergistic effects with gemcitabine, 5-fluorouracil, and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKα was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKα did not relate to survival, nuclear CHKα distribution was observed in 43% of samples and was associated with longer survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKα inhibitors, we cultured IMIM-PC-2 cells with increasingly higher concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified upregulation of ABCB1 and ABCB4 multidrug resistance transporters, and functional studies confirmed that their upregulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKα inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response.
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mazarico
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain. preal@cnio.es vjsanchez@cnio.es.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Sánchez-Arévalo Lobo
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Rosy
authors.initials: R
authors.lastname: Favicchio
authors.affiliation: The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.affiliation: The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Carrillo-de Santa Pau
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Marqués
authors.affiliation: Division of Translational Oncology, Department of Oncology, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Lacal
authors.affiliation: Comprehensive Cancer Imaging Centre, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Aboagye
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid, Spain. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. preal@cnio.es vjsanchez@cnio.es.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002073:Butanes / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002797:Choline Kinase / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: C507944:1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide; D014408:Biomarkers, Tumor; D002073:Butanes; D004791:Enzyme Inhibitors; D011726:Pyridinium Compounds; C517212:CHKA protein, human; D002797:Choline Kinase