American Association for Cancer Research
15357163mct150214-sup-146678_1_supp_3167959_nw2khc.png (179.48 kB)

Supplementary Figure 5 from Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors

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posted on 2023-04-03, 14:49 authored by José M. Mazarico, Victor J. Sánchez-Arévalo Lobo, Rosy Favicchio, William Greenhalf, Eithne Costello, Enrique Carrillo-de Santa Pau, Miriam Marqués, Juan C. Lacal, Eric Aboagye, Francisco X. Real

RNA-Seq analysis of IMIM-PC-2 and IMIM-PC-2-R cells


EU 7th Framework Programme

Ministerio de Economía y Competitividad

Instituto de SaludCarlos III

NIHR Liverpool Pancreas Biomedical Research Unit, Cancer Research UK, and Pancreatic Cancer UK

Instituto de Salud Carlos III



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. Mol Cancer Ther; 15(2); 323–33. ©2016 AACR.