Salt-inducible kinases as druggable targets for immunotherapy of ovarian cancer

Malignant ascites strongly inhibits T cell anti-tumor responses in patients with high-grade serous ovarian cancer (HGSOC). Using an all-human high-throughput drug repurposing screen, we identified salt-inducible kinases (SIKs) as negative regulators of T cell function in ascites.

Pharmacological inhibition or genetic depletion of SIK2 and SIK3 in T cells strongly upregulates anti-tumor immunity and improves survival in immunotherapy-resistant preclinical models. Song, M.

et al. IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.

Nature 562 , 423–428 (2018). A research article that presents the roles of HGSOC ascitic fluid in suppressing T cell early activation and effector function.

Vazquez-Garcia, I. et al.

Ovarian cancer mutational processes drive site-specific immune evasion. Nature 612 , 778–786 (2022).

This paper reports multi-omic cellular phenotype data on the HGSOC TME. Zhou, J.

et al. A novel compound ARN-3236 inhibits salt-inducible kinase 2 and sensitizes ovarian cancer cell lines and xenografts to paclitaxel.

Clin. Cancer Res.

23 , 1945–1954 (2017). This paper presents SIK2 as a promising druggable target against ovarian cancer cells.

Sundberg, T. B.

et al.