Abstract 4258: Targeting MGAT5B-mediated glycosylation of kinase receptors for the treatment of malignant peripheral nerve sheath tumors and RAS-related malignancies.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that occur either sporadically or in patients with Neurofibromatosis type I. Surgery is the main stay of treatment, however, due to the invasive growth, propensity to metastasis, limited sensitivity to chemotherapy and radiation, 5-year survival rates is only 20%-50%. Recent work has identified several altered intracellular signal transduction cascades and deregulated kinase receptors, posing the possibility of personalized, targeted therapeutics. Kinase receptors depend on the glycosylation for stabilization, maturation, transportation onto the cell surface, phosphorylation and activation, and aberrant glycosylation to stabilize the expression of kinase receptors on the cell surface is associated with cancers. The appropriate and accurate modification of glycan to proteins mainly depends on the action of highly specific and precisely located enzymes known as glycosyltransferases and glycosidases in different tissues and cells. In this report, glycoproteins were highly expressed in MPNST cell lines compared with normal Schwann cells (NSC). Human Glycosylation PCR Array was used to profile the expression of 84 key genes encoding enzymes to regulate the glycosylation of proteins. Compared with NSC, we did not find any change in the mRNA expression levels of glycosidases, however, multiple glycosyltransferases (B4GALT5, FUT8, MGAT3, MGAT4A, MGAT5, MGAT5B, GALNT13, GALNT14, POMT1, ST8SIA2) were overexpressed in some MPNST cell lines, especially MGAT5B, one of glycosyltransferases to promote N-linked or O-linked glycosylation of proteins was highly expressed in MPNST cell lines and clinical specimens, and colon and pancreatic cancer cell lines with K-ras mutations. Exogenous expressing K-ras (G12V) significantly upregulated the expression of MGAT5B. The expression levels of MGAT5B were correlated with RAS kinase activity. We also found AKT interacted with MGAT5B and phosphorylation of S192 of MGAT5B promoted transportation from the cytoplasm into the Golgi apparatus and mutated MGAT5BS192A expression was distributed in the ER and cytoplasm. Experimental tumor lung metastasis was significantly inhibited in MPNST cells expressing MGAT5BS192A. Furthermore, we found that transient or stable knockdown of MGAT5B significantly attenuated the glycosylation and phosphorylation of kinase receptors to block their signaling, arrested cells in G1 phase and altered the morphology of MPNST cell lines. Taken together, these data suggest that RAS-driving the expression of MGAT5B plays a critical role in promoting glycosylation of kinase receptors to mediate their intracellular signaling and targeting MGAT5B-mediated glycosylation of kinase receptors may open a new therapeutic window for MPNSTs and RAS-related malignancies Citation Format: Quansheng Zhu, Yechun Song, Hui Shang, Thresa Nguyen, Svetlana Bolshakov, Xiaoyan Ma, Alexander Lazar, Raphael Pollock, Dina Chelouche Lev. Targeting MGAT5B-mediated glycosylation of kinase receptors for the treatment of malignant peripheral nerve sheath tumors and RAS-related malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4258. doi:10.1158/1538-7445.AM2013-4258