Longitudinal Expression Response Of Glycosylation Related Genes, Regulators, And Targets In Cancer Cell Lines Treated With Eleven Anti-Tumor Agents

Cancer cells have profound alterations in glycosylation processes, which affects the functioning of malignant cells and their interaction with surrounding environment. We examined the effects of treatment of cancer cell lines with eleven antitumor agents (bortezomib, cisplatin, dasatinib, doxorubicin, erlotinib, gemcitabine, paclitaxel, sirolimus, sorafenib, sunitinib, and topotecan) on transcriptional changes in 179 candidate genes involved in biochemical glycosylation pathways or encoding glycosylation targets, regulators of glycosylation processes, and components of cancer pathways affected by glycosylation. In order to achieve this goal, we analyzed time course gene expression information for the NCI-60 cancer cell line panel using the data from the NCI Transcriptional Pharmacodynamic Workbench (NCI TPW), a resource developed at the National Cancer Institute. Our analysis identified 145 glycosylation related genes that responded to drug treatment in a concerted manner. Many of these genes had a concerted response to multiple agents; however, the direction and the magnitude of concerted response were specific to individual drugs. Expression of multiple genes prior to treatment and/or transcriptional changes in response to treatment were significantly correlated with drug chemosensitivity, measured as log(GI50). Treatment with dasatinib resulted in the largest number of significant correlations of chemosensitivity with gene expression prior to treatment and with gene expression changes in response to treatment. Significant correlations of transcriptional changes after treatment and/or of pre-treatment gene expression levels of glycosylation related genes and glycosylation targets were also observed for other antitumor agents. Chemosensitivity to kinase inhibitors and DNA damaging agents was significantly correlated with expression of genes involved in N- and O-glycosylation, fucosylation, biosynthesis of poly-N-acetyllactosamine, removal of misfolded proteins, binding to hyaluronic acid and other glycans, and cell adhesion. In particular, tumor cell sensitivity or resistance to multiple agents were significantly correlated with changes in expression of C1GALT1C1 (COSMC), FUCA1, SDC1, MUC1, members of the MGAT, GALNT, B4GALT, B3GNT, MAN, and EDEM gene families, and other genes involved in glycosylation processes or encoding glycosylation targets and signaling regulators. We present a catalog of dynamic concerted changes in expression of glycosylation related genes, their ligands, regulators, and targets in response to chemotherapy, and provide a list of genes that influence the strength of response of cancer cells to treatment. These glycosylation related genes may be considered as potential candidates for drug targeting in combination therapy to enhance the effects of treatment. Funded by NCI Contract No. HHSN261200800001E. Citation Format: Julia Krushkal, Yingdong Zhao, Curtis Hose, Anne Monks, James H. Doroshow, Richard Simon. Longitudinal expression response of glycosylation related genes, regulators, and targets in cancer cell lines treated with eleven anti-tumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1557. doi:10.1158/1538-7445.AM2017-1557