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|Ref Type||Journal Article|
|Authors||Mazarico JM, Sánchez-Arévalo Lobo VJ, Favicchio R, Greenhalf W, Costello E, Carrillo-de Santa Pau E, Marqués M, Lacal JC, Aboagye E, Real FX|
|Title||Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|MN58b||MN58b inhibits choline kinase alpha (CHKA), resulting in decreased growth and increased apoptosis of tumor cells with high CHKA expression (PMID: 26769123, PMID: 28157707).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||pancreatic ductal adenocarcinoma||not applicable||MN58b + Oxaliplatin||Preclinical||Actionable||In a preclinical study, the combination of MN58b and Eloxatin (oxaliplatin) worked synergistically to inhibit growth of pancreatic ductal adenocarcinoma cell lines in culture (PMID: 26769123).||26769123|
|Unknown unknown||pancreatic ductal adenocarcinoma||not applicable||Fluorouracil + MN58b||Preclinical||Actionable||In a preclinical study, MN58b and Adrucil (fluorouracil) in combination demonstrated an additive effect on growth inhibition of pancreatic ductal adenocarcinoma cell lines in culture (PMID: 26769123).||26769123|
|Unknown unknown||pancreatic ductal adenocarcinoma||not applicable||Gemcitabine + MN58b||Preclinical||Actionable||In a preclinical study, MN58b and Gemzar (gemcitabine) in combination demonstrated an additive effect on growth inhibition of pancreatic ductal adenocarcinoma cell lines in culture (PMID: 26769123).||26769123|