Salt-inducible kinase inhibition suppresses acute myeloid leukemia progression in vivo

Tarumoto, Yusuke; Lin, Shuo; Wang, Jinhua; Milazzo, Joseph P.; Xu, Yali; Lü, Bin; Yang, Zhaolin; Wei, Yiliang; Polyanskaya, Sofya A.; Wunderlich, Mark; Gray, Nathanael S.; Stegmaier, Kimberly; Vakoc, Christopher R.

doi:10.1182/blood.2019001576

Cited by 56 publications

(45 citation statements)

References 72 publications

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“…156 It was also reported that a single point mutation of SIK3 (T142Q) or the inactivation of HDAC4 were enough to acquire the resistance to the YKL-05-099 treatment. 156 MRT-199665 is developed as an effective, ATP competitive, selective MARK/SIK/AMPK inhibitor. 8 MRT-199665 inhibits SIKmediated CRTC3 phosphorylation to increase LPS-stimulated IL-10 production and inhibit the secretion of proinflammatory cytokines, such as IL-6, IL-12, and TNFα in macrophages.…”

Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

“…160,161 Crenolanib has been found to have a strong nontargeting effect on SIK (IC 50 in vivo for SIK2 is 16 nM, for SIK3 is 2 nM), and shows good tolerance in human patients. 156 Staurosporine is likely to inhibit both SIK1 and SIK2 functions, and further considered as a nonselective kinase inhibitor at high concentrations to repress many kinases, including PKC, CaMK. 162,163 Staurosporine also increases CRTC2 abundance in nucleus and triggers CRH transcription in 4B cells by repressing SIKs.…”

Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

“…YKL-05-099 can also alleviate the disease progression in vivo and prolong the survival of the animals at a well-tolerated dose upon treating two different MLL-AF9 acute myeloid leukemia mouse models. 156 It was also reported that a single point mutation of SIK3 (T142Q) or the inactivation of HDAC4 were enough to acquire the resistance to the YKL-05-099 treatment. 156

Fig.…”

Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

“… 156 It was also reported that a single point mutation of SIK3 (T142Q) or the inactivation of HDAC4 were enough to acquire the resistance to the YKL-05-099 treatment. 156

Fig. 5 Potential inhibitors targeting SIKs.…”

Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

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The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis

Sun

Jiang

et al. 2020

Sig Transduct Target Ther

103

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Salt-inducible kinases (SIKs) belong to AMP-activated protein kinase (AMPK) family, and functions mainly involve in regulating energy response-related physiological processes, such as gluconeogenesis and lipid metabolism. However, compared with another well-established energy-response kinase AMPK, SIK roles in human diseases, especially in diabetes and tumorigenesis, are rarely investigated. Recently, the pilot roles of SIKs in tumorigenesis have begun to attract more attention due to the finding that the tumor suppressor role of LKB1 in non-small-cell lung cancers (NSCLCs) is unexpectedly mediated by the SIK but not AMPK kinases. Thus, here we tend to comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for SIKs, and shed light on SIKs as the potential therapeutic targets for cancer therapies.

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Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

Fig.…”

Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

“… 156 It was also reported that a single point mutation of SIK3 (T142Q) or the inactivation of HDAC4 were enough to acquire the resistance to the YKL-05-099 treatment. 156

Fig. 5 Potential inhibitors targeting SIKs.…”

Section: Potential Inhibitors Targeting Siksmentioning

confidence: 99%

See 2 more Smart Citations

The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis

Sun

Jiang

et al. 2020

Sig Transduct Target Ther

103

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“…We tested small molecule drugs targeting the ETS-factors ELK3, or ERG and FLI1 in dexamethasone resistant E/R+ REH cells and found reduced cell viability with sub-micromolar concentration. Inhibitors abrogating FLI1, MEF2C, ELK3, or SP4 activation have been previously shown to have efficacy in different cancers [94][95][96][97][98][99]. Moreover, the small molecule ERG/FLI1 inhibitor tested here has entered a phase 1 study in Ewing sarcoma [100].…”

Section: Single Cell Profiling Techniques Have Challenged How We Defimentioning

confidence: 99%

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

Mehtonen

Teppo

Lahnalampi

et al. 2020

Preprint

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Tight regulatory loops orchestrate commitment to B-cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention.We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion.We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment-resistance, we show that selective inhibitors of ETS-transcription factors could effectively reduce cell viability.Our data provide a detailed picture of the transcription factor activities that characterize both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.

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SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA‐deficient cells

et al. 2021

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The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here we performed a kinome-wide synthetic lethality screen in FANCA-/-fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA-deficient cells. Among these kinases, we identified the depletion of the centrosome kinase SIK2 as synthetic lethal upon loss of FANCA. We found that FANCA co-localizes with SIK2 at multiple mitotic structures and regulates the activity of SIK2 at centrosomes. Furthermore, we found that loss of FANCA exacerbates cell cycle defects induced by pharmacological inhibition of SIK2, including impaired G2-M transition, delayed mitotic progression, and cytokinesis failure. In addition, we showed that inhibition of SIK2 abrogates nocodazole-induced prometaphase arrest, suggesting a novel role for SIK2 in the spindle assembly checkpoint. Together, these findings demonstrate that FANCA-deficient cells are dependent upon SIK2 for survival, supporting a preclinical rationale for targeting of SIK2 in FA-disrupted cancers.

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Salt-inducible kinase inhibition suppresses acute myeloid leukemia progression in vivo

Cited by 56 publications

References 72 publications

The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis

The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA‐deficient cells

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