title: WEE1 inhibition alleviates resistance to immune attack of tumor cells undergoing epithelial-mesenchymal transition.
abstract: Aberrant expression of the T-box transcription factor brachyury in human carcinomas drives the phenomenon of epithelial-mesenchymal transition (EMT), a phenotypic modulation that facilitates tumor dissemination and resistance to conventional therapies, including chemotherapy and radiotherapy. By generating isogenic cancer cell lines with various levels of brachyury expression, we demonstrate that high levels of brachyury also significantly reduce the susceptibility of cancer cells to lysis by both antigen-specific T cells and natural killer cells. Our results indicated that resistance of brachyury-high tumor cells to immune-mediated attack was due to inefficient caspase-dependent apoptosis, manifested as inefficient nuclear lamin degradation in the presence of activated effector caspases. We correlated this phenomenon with loss of cell-cycle-dependent kinase 1 (CDK1), which mediates lamin phosphorylation. In support of a causal connection, pretreatment of tumor cells with a specific inhibitor of WEE1, a negative regulator kinase of CDK1, could counter the defective apoptosis of tumor cells expressing high levels of brachyury. Thus, our findings suggested that reconstituting CDK1 activity to threshold levels may be sufficient to restore immunosurveillance of mesenchymal-like cancer cells that have escaped previous immune detection or eradication.
authors.affiliation: Authors' Affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Duane H
authors.initials: DH
authors.lastname: Hamilton
authors.forename: Bruce
authors.initials: B
authors.lastname: Huang
authors.forename: Romaine I
authors.initials: RI
authors.lastname: Fernando
authors.forename: Kwong-Yok
authors.initials: KY
authors.lastname: Tsang
authors.forename: Claudia
authors.initials: C
authors.lastname: Palena
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D005326:Fetal Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D020825:T-Box Domain Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000502:physiology; D019139:Tumor Escape; D000098908:Brachyury Protein
chemical_list: D000970:Antineoplastic Agents; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D005326:Fetal Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C499349:WEE1 protein, human; C549567:adavosertib