Inhibition of salt inducible kinases reprograms T cells and antitumor immunity in ovarian cancer
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PROVIDER: PRJNA1144154 | ENA |
REPOSITORIES: ENA
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Project description:Patients with metastatic high grade serous ovarian carcinoma (HGSOC) are often unresponsive to immunotherapies; here, we identify salt-inducible kinases (SIK) as a key driver of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, while SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant HGSOC, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2/3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-g, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.
2026-03-31 | GSE275654 | GEO
Project description:Inhibition of salt inducible kinases reprograms T cells and antitumor immunity in ovarian cancer
| PRJNA1152508 | ENA
Project description:Patients with metastatic high grade serous ovarian carcinoma (HGSOC) are often unresponsive to immunotherapies due to a hostile tumor microenvironment (TME). To identify the main drivers of immunosuppression, we performed an all-human functional screen of 4,292 druggable small molecules in the presence of malignant ascites from patients with HGSOC. Salt-inducible kinases (SIK) emerged as top targets that block human T cell antitumor activity. We saw that when cultured with cell-free patient ascites, primary human T cells express high levels of SIK. Administration of SIK inhibitors, YKL-05-099 or ARN-3236, consistently demonstrated therapeutic efficacy and survival advantages in syngeneic mouse models of resistant HGSOC. The encouraging outcomes from pharmaceutical inhibition of SIK were recapitulated by genetic depletion of Sik2/Sik3 in immunocompetent mice bearing HGSOC. In contrast, SIK inhibition in T cell-depleted hosts was ineffective, establishing T cell-centered antitumor immunity as the primary mechanism of action. Mechanistically, bulk transcriptomic analysis of tumor cells from SIK inhibitor-treated mice showed reduced disease progression along with upregulation of interferon-stimulated genes, while single-cell transcriptomic analysis of matched immune TME populations demonstrated increased infiltration of CD8 and CD4 T cells with enhanced cytotoxicity and effector cytokine function. Molecular studies in primary T cells identified in vivo target genes responsible for SIK-induced dysfunction including upregulation of TXNIP (Thioredoxin- Interacting Protein) and ZFP36L2 (ZFP36 Ring Finger Protein Like 2), negative regulators of effector cell metabolism and IFN-g cytokine production. We also observed downregulation of LYST and VPS37B, critical in cytotoxic granzyme biogenesis and trafficking. In contrast to PD-1 blockade alone that does not improve survival, combination of SIK inhibitors with immune checkpoint blockers significantly increased survival of mice with HGSOC. While T cells are the essential targets of SIK inhibitors, we noted that SIK inhibition boosted innate immunity including enhancing antigen presentation by dendritic cells. Spatial proteomic analysis (CODEX) in the presence of SIK inhibition further revealed a shift from immunosuppressive to immunostimulatory cellular neighborhoods. Our studies identify SIK as a key driver of immunosuppression in HGSOC. Treatment with SIK inhibitor alone or combined with PD-1 blockade may increase the survival of patients with ovarian cancer.
2026-03-31 | GSE273961 | GEO
Project description:LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia
| PRJNA431204 | ENA
Project description:LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (RNA-Seq)
| PRJNA431335 | ENA
Project description:LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (ChIP-Seq)
| PRJNA431217 | ENA
Project description:Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP‑activated protein kinase family. They are expressed ubiquitously in humans. Under normal circumstances, SIK1 regulates adrenocortical function in response to high salt or adrenocorticotropic hormone stimulation, SIK2 is involved in cell metabolism, controlling insulin signaling and gluconeogenesis and SIK3 coordinates with the mTOR complex, promoting cancer. The dysregulation of SIKs has been widely detected in various types of cancers. Based on most of the existing studies, SIK1 is mostly considered a tumor inhibitor, SIK2 and SIK3 are usually associated with tumor promotion. However, the functions of SIKs have shown contradictory in certain tumors, suggesting that SIKs cannot be simply classified as oncogenes or tumor suppressor genes. The present review provided a comprehensive summary of the roles of SIKs in the initiation and progression of different cancers, aiming to elucidate their clinical value and discuss potential strategies for targeting SIKs in cancer therapy.
| S-EPMC10546379 | biostudies-literature
Project description:Cold-inducible brown fat thermogenesis enhances MHC class I expression and antitumor immunity in ovarian cancer.
| PRJNA1102423 | ENA
Project description:Osteoclasts are large multinucleated cells responsible for bone resorption. Excessive inflammatory activation of osteoclasts leads to bony erosions, which are the hallmark of several diseases such as rheumatoid arthritis (RA). Salt-inducible kinases (SIK) constitute a subfamily of kinases comprising three members (SIK1, -2, and -3). Inhibition of SIK kinase activity induces an anti-inflammatory phenotype in macrophages. Since osteoclasts originate from precursors of macrophage origin, we hypothesized a role of SIK in osteoclastogenesis. We analyzed SIK1, -2 and -3 expression and function in osteoclast differentiation using the mouse macrophage cell line RAW264.7 and bone marrow-derived macrophages (BMM). We show that all three SIK are expressed in fully differentiated osteoclasts and that in BMM-derived osteoclasts there is an increased expression of SIK1 and SIK3 proteins. Interestingly, the pan-SIK inhibitor HG-9-91-01 significantly inhibited osteoclastogenesis by dose dependently reducing osteoclast differentiation markers (i.e. CathepsinK, MMP-9 and TRAP) and bone resorbing activity. Analysis of the signaling pathways activated by RANKL in RAW cells showed that SIK inhibitors did not affect RANKL-induced ERK1/2, JNK, p38 or NF-κB activation, but induced a significant downregulation in c-Fos and NFATc1 protein levels, the two main transcription factors involved in the regulation of osteoclast-specific genes. Moreover, SIK inhibition partially increased the proteasome-mediated degradation of c-Fos. SIK2 and SIK3 knockout RAW cells were generated by the CRISPR/Cas9 approach. SIK2 KO and, to a lesser extent, SIK3 KO recapitulated the effect of SIK small molecule inhibitor, thus confirming the specificity of the effect of SIK inhibition on the reduction of osteoclastogenesis. Overall, our results support the notion that the SIK signaling pathway plays a significant role among the check-points controlling osteoclastogenesis. SIK kinase inhibitors could thus represent a potential novel therapy to prevent bone erosions.
| S-EPMC5626034 | biostudies-literature
Project description:The salt-inducible kinases, SIK1, SIK2 and SIK3, most closely resemble the AMP-activated protein kinase (AMPK) and other AMPK-related kinases, and like these family members they require phosphorylation by LKB1 to be catalytically active. However, unlike other AMPK-related kinases they are phosphorylated by cyclic AMP-dependent protein kinase (PKA), which promotes their binding to 14-3-3 proteins and inactivation. The most well-established substrates of the SIKs are the CREB-regulated transcriptional co-activators (CRTCs), and the Class 2a histone deacetylases (HDAC4/5/7/9). Phosphorylation by SIKs promotes the translocation of CRTCs and Class 2a HDACs to the cytoplasm and their binding to 14-3-3s, preventing them from regulating their nuclear binding partners, the transcription factors CREB and MEF2. This process is reversed by PKA-dependent inactivation of the SIKs leading to dephosphorylation of CRTCs and Class 2a HDACs and their re-entry into the nucleus. Through the reversible regulation of these substrates and others that have not yet been identified, the SIKs regulate many physiological processes ranging from innate immunity, circadian rhythms and bone formation, to skin pigmentation and metabolism. This review summarises current knowledge of the SIKs and the evidence underpinning these findings, and discusses the therapeutic potential of SIK inhibitors for the treatment of disease.
| S-EPMC8057676 | biostudies-literature