The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy

Liu, Suhu; Marneth, Anna E.; Alexe, Gabriela; Walker, Sarah R.; Gandler, Helen; Ye, Darwin Q.; Labella, Katherine; Mathur, Radhika; Toniolo, Patricia A.; Tillgren, Michelle; Gokhale, Prafulla C.; Barbie, David A.; Mullally, Ann; Stegmaier, Kimberly; Frank, David A.

doi:10.1182/bloodadvances.2018016733

Cited by 26 publications

(17 citation statements)

References 38 publications

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“…However, to our current knowledge there are no clinical trials investigating YB-1 as a marker in gynecological cancer. However, knowledge is emerging that momelotinib (CYT387), a pharmacological inhibitor of noncanonical IkB kinase/TANK-binding kinase 1 (IKBKE/TBK1) which is used in acute myeloid leukemia, might be able to regulate tumor MYC-dependent survival through YB-1 [9,23]. This opens new pathways of investigation for the enhancement of current mTOR inhibition or YB-1 regulation.…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

Sobočan

Bračič

Knez

et al. 2020

Cancers

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Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin.

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Section: Ongoing Clinical Trialsmentioning

confidence: 99%

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

Sobočan

Bračič

Knez

et al. 2020

Cancers

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“…ROCK1 KO downregulates both the yellow and red modules, and ROCK inhibition has been shown to inhibit cell growth in FLT3 mutant AML patient-derived blasts [ 37 ]. We predict that TBK1 KO downregulates the red module; it has previously been suggested as a therapeutic target in AML due to its activation of MYC-dependent survival pathways [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Data-Driven Math Model of FLT3-ITD Acute Myeloid Leukemia Reveals Potential Therapeutic Targets

Wooten

Gebru

Wang

et al. 2021

JPM

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FLT3-mutant acute myeloid leukemia (AML) is an aggressive form of leukemia with poor prognosis. Treatment with FLT3 inhibitors frequently produces a clinical response, but the disease nevertheless often recurs. Recent studies have revealed system-wide gene expression changes in FLT3-mutant AML cell lines in response to drug treatment. Here we sought a systems-level understanding of how these cells mediate these drug-induced changes. Using RNAseq data from AML cells with an internal tandem duplication FLT3 mutation (FLT3-ITD) under six drug treatment conditions including quizartinib and dexamethasone, we identified seven distinct gene programs representing diverse biological processes involved in AML drug-induced changes. Based on the literature knowledge about genes from these modules, along with public gene regulatory network databases, we constructed a network of FLT3-ITD AML. Applying the BooleaBayes algorithm to this network and the RNAseq data, we created a probabilistic, data-driven dynamical model of acquired resistance to these drugs. Analysis of this model reveals several interventions that may disrupt targeted parts of the system-wide drug response. We anticipate co-targeting these points may result in synergistic treatments that can overcome resistance and prevent eventual recurrence.

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“…Although limited data exist concerning the effectiveness of Momelotinib in AML, it has been shown to effectively inhibit the growth of AML cell lines and disease progression in a xenograft model. Interestingly, the anti-leukemic effect was attributed to the inhibition of the kinase IKBKE, a noncanonical IkB kinase, which drives MYC expression [144]. Momelotinib, similarly to other JAK2 inhibitors, also shows inhibitory activity against FLT3.…”

Section: Jak Inhibitorsmentioning

confidence: 99%

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

Moser¹,

Edtmayer²,

Witalisz-Siepracka³

et al. 2021

Biomedicines

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Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.

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The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy

Cited by 26 publications

References 38 publications

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

Data-Driven Math Model of FLT3-ITD Acute Myeloid Leukemia Reveals Potential Therapeutic Targets

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

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