TTK inhibitor OSU13 promotes immunotherapy responses by activating tumor STING.
JCI Insight
; 2024 Jun 20.
Article
em En
| MEDLINE
| ID: mdl-38900577
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
JCI Insight
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos