The phenomenon of epithelial-mesenchymal transition (EMT) is a phenotypic switch that allows epithelial tumor cells to acquire features of mesenchymal cells, including the ability to migrate and invade and, therefore, to disseminate from the primary site. In addition to promoting tumor dissemination, various reports have demonstrated that acquisition of features of EMT associates with tumor resistance to the cytotoxic effects of chemotherapy, radiation, and some targeted therapies. It is not well understood, however, the contribution of EMT to the escape of tumors from host immune-surveillance and immune-mediated rejection. Our laboratory has characterized the T-box transcription factor brachyury as a tumor-associated antigen and a regulator of EMT in human carcinomas. By generating isogenic cancer cell lines with various levels of brachyury expression, we demonstrated that high levels of brachyury significantly reduce the susceptibility of cancer cells to lysis by both antigen-specific T cells and natural killer cells, and render tumor cells less responsive to a cancer vaccine in syngeneic murine tumor models. This resistance was due to inefficient caspase-dependent apoptosis, manifested as inefficient nuclear lamin degradation in the presence of activated effector caspases. We correlated this phenomenon to loss of cell cycle kinase CDK1, which mediates lamin phosphorylation. In support of a causal connection, pre-treatment of tumor cells with MK-1775, a specific inhibitor of WEE1, which is known to be a negative regulator kinase of CDK1 activity, could counter the defective apoptosis of tumor cells expressing high levels of brachyury. Thus, our findings suggest reconstituting CDK1 activity to threshold levels might be sufficient to elevate immune-mediated lysis of mesenchymal-like cancer cells, and improve the efficacy of anti-tumor vaccines.
Citation Format: Duane H. Hamilton, Romaine I. Fernando, Kwong-Yok Tsang, Claudia Palena. MK-1775, a WEE1 inhibitor alleviates resistance to immune attack of tumor cells undergoing an epithelial-mesenchymal transition. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A42.
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