Choline Kinase Alpha (CHK alpha) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors

摘要

Choline kinase a (CHK alpha) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHK alpha in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHK alpha expression, associated with differentiation. CHK alpha protein expression was directly correlated with sensitivity to MN58b, a CHK alpha inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHK alpha knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHK alpha 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, CHK alpha was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHK alpha did not relate to survival, nuclear CHK alpha 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 CHK alpha 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 CHK alpha inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response. (C)2016 AACR.