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Choline kinase alpha (CHKA) as a therapeutic target in pancreatic ductal adenocarcinoma: Expression, predictive value, and sensitivity to inhibitors

ABSTRACT: Choline kinase alpha (CHKA) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKA in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKA expression and a good correlation between protein expression and sensitivity to MN58b, a CHKA inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKA knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKA inhibition and, in vitro, MN58b had synergistic effects with gemcitabine, 5-fluorouracil and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKA was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKA did not relate to survival, nuclear CHKA distribution was observed in 43% of samples and was associated with survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKA inhibitors, we cultured IMIM-PC-2 cells with continuous incremental concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified up-regulation of ABCB1 and ABCB4 multidrug resistance transporters and functional studies confirmed that their up-regulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKA inhibition merits further attention as a therapeutic option in patients with PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60321 | GEO | 2017/08/11

SECONDARY ACCESSION(S): PRJNA258026

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC. Pancreatic ductal adenocarcinoma xenografts were grown in Athymic Nude-Foxn1nu mice. RNA was extracted and profiled in Affymetrix platform to identify genes correlating with sensitivity to MRK-003

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Choline kinase alpha (CHKA) as a therapeutic target in pancreatic ductal adenocarcinoma: Expression, predictive value, and sensitivity to inhibitors

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