ResearchIn-Press PreviewOncology
Open Access | 10.1172/jci.insight.177523
1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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1Department of Pathology, The Ohio State University, Columbus, United States of America
2Department of Pathology and Dermatology, The Ohio State University, Columbus, United States of America
3Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America
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Published June 20, 2024 - More info
TTK (MPS1) spindle assembly checkpoint kinase is an emerging cancer target. This preclinical study explored the anti-tumor mechanism of TTK inhibitor OSU13 to define a strategy for clinical development. We observed prominent anti-tumor activity of OSU13 in melanoma, colon, and breast cancer cells, melanoma patient-derived organoids, and mice bearing colon tumors associated with G2 cell cycle arrest, senescence, and apoptosis. OSU13-treated cells displayed DNA damage and micronuclei that triggered the cytosolic DNA-sensing cGAS-STING pathway. STING was required for the induction of several proteins involved in T cell recruitment and activity. Tumors from OSU13-treated mice showed an increased proportion of T and NK cells and evidence of PD-1/PD-L1 immune checkpoint activation. Combining a low-toxicity dose of OSU13 with anti-PD1 checkpoint blockade resulted in prominent STING- and CD8 T cell-dependent tumor inhibition and improved survival. These findings provide a rationale for utilizing TTK inhibitors in combination with immunotherapy in STING-proficient tumors.