Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells

Boudný, Miroslav; Zemanová, Jana; Khirsariya, Prashant; Borský, Marek; Verner, Jan; Černá, Jana; Oltová, Alexandra; Šeda, Václav; Mráz, Marek; Jaroš, Josef; Jašková, Zuzana; Špunarová, Michaela; Brychtová, Yvona; Souček, Karel; Drápela, Stanislav; Kasparkova, Marie; Mayer, Jiřı́; Paruch, Kamil; Trbušek, Martin

doi:10.3324/haematol.2018.203430

Cited by 23 publications

(21 citation statements)

References 51 publications

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“…Preliminary results suggest that in p53 or ATM defective CLL cells, inhibition of ATR signaling by the AZD6738 small molecule leads to an accumulation of unrepaired DNA damage, which is carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe [95]. Similar results have also been obtained by the inhibition of the CHK1 protein [96].…”

Section: Other Mechanisms That Enhance Cell Death In Tp53 Disrupted Cmentioning

confidence: 60%

Section: Other Mechanisms That Enhance Cell Death In Tp53 Disrupted Cmentioning

confidence: 99%

“…Another strategy to overcome TP53 disfunction may stem from the concept of 'synthetic lethality' [95,96]. Synthetic lethality is based on the fact that p53 deficient cells lack a functional G1/S checkpoint and therefore fully depend on the remaining checkpoints, mainly controlled by the ataxia telangiectasia and Rad3-related (ATR) protein and by the checkpoint kinase 1 (CHK1) which can be utilized by targeted inhibition [95,96]. Preliminary results suggest that in p53 or ATM defective CLL cells, inhibition of ATR signaling by the AZD6738 small molecule leads to an accumulation of unrepaired DNA damage, which is carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe [95].…”

Section: Other Mechanisms That Enhance Cell Death In Tp53 Disrupted Cmentioning

confidence: 99%

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Targeting p53 in chronic lymphocytic leukemia

Moia

Boggione

Mahmoud

et al. 2020

Expert Opinion on Therapeutic Targets

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Introduction: Genomic studies have allowed to identify molecular predictors for chronic lymphocytic leukemia (CLL) treatment tailoring. TP53 disruption is the strongest predictor of chemo-refractoriness and its assessment is the first decisional node in the disease treatment algorithm. Areas covered: The review covers the p53 biological pathway, its genetic alterations and clinical implications in CLL, and its druggable targets. The potential therapeutic options for TP53 disrupted patients are described, including: i) agents circumventing TP53 disruption; ii) targeted therapies restoring the physiological function of mutant p53; and iii) medicines potentiating p53 function. Expert opinion: The key approach to improve CLL outcome is treatment tailoring in individual patients. BCR and BCL2 inhibitors have significantly improved CLL survival, however TP53 disrupted patients still have a less favorable outcome than wild type cases, possibly because these novel drugs do not directly target p53 and do not restore the function of the disrupted p53 pathway. Emerging innovative molecules in cancer are able to restore the p53 mutant protein and/or potentiate the activity of the p53 wild type protein. If these compounds were confirmed as efficacious also for CLL, they would represent another step forward in the care of high risk CLL patients with TP53 abnormalities.

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Section: Other Mechanisms That Enhance Cell Death In Tp53 Disrupted Cmentioning

confidence: 60%

Section: Other Mechanisms That Enhance Cell Death In Tp53 Disrupted Cmentioning

confidence: 99%

Section: Other Mechanisms That Enhance Cell Death In Tp53 Disrupted Cmentioning

confidence: 99%

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Targeting p53 in chronic lymphocytic leukemia

Moia

Boggione

Mahmoud

et al. 2020

Expert Opinion on Therapeutic Targets

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“…The activated Chk1 transfers into the nucleus to prevent new source excitation [47]. For hematopoietic tumors, Miroslav et al had shown that Chk1 was a key protein in the development of B cell lymphoma [48]. As a member of the histone H2A family, H2AX is a key promoter that amplifies signals in the early stages of DNA damage and continuously recruits repair factors to nuclear foci [49].…”

Section: Discussionmentioning

confidence: 99%

AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma

et al. 2021

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“…The next-generation sequencing technologies led to identification of additional genetic aberrations in CLL, such as mutations in NOTCH1, SF3B1 , and BIRC3 , which can be considered as prognostic and predictive biomarkers. 41 The NOTCH genes encode transmembrane proteins NOTCH1 to NOTCH4, that function as transcription factors, modifying the expression of numerous target genes, such as MYC and NF-kB signalling components. 21 NOTCH1 mutations occur in 4% to 11% of CLL patients and are frequently correlated with trisomy 12 and unmutated IGHV genes.…”

Section: Cll Prognostic Factorsmentioning

confidence: 99%

Therapeutic Options for Patients with TP53 Deficient Chronic Lymphocytic Leukemia: Narrative Review

Stefaniuk¹,

Onyszczuk²,

Szymczyk³

et al. 2021

CMAR

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Chronic lymphocytic leukemia (CLL), which is the most common type of leukemia in western countries in adults, is characterized by heterogeneity in clinical course, prognosis and response to the treatment. Although, in recent years a number of factors with probable prognostic value in CLL have been identified (eg NOTCH1, SF3B1 and BIRC-3 mutations, or evaluation of microRNA expression), TP53 aberrations are still the most important single factors of poor prognosis. It was found that approximately 30% of all TP53 defects are mutations lacking 17p13 deletion, whereas sole 17p13 deletion with the absence of TP53 mutation consists of 10% of all TP53 defects. The detection of del(17)(p13) and/or TP53 mutation is not a criterion itself for starting antileukemic therapy, but it is associated with an aggressive course of the disease and poor response to the standard chemoimmunotherapy. Treatment of patients with CLL harbouring TP53- deficiency requires drugs that promote cell death independently of TP53 . Novel and smarter therapies revolutionize the treatment of del(17p) and/or aberrant TP53 CLL, but development of alternative therapeutic approaches still remains an issue of critical importance.

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Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells

Cited by 23 publications

References 51 publications

Targeting p53 in chronic lymphocytic leukemia

Targeting p53 in chronic lymphocytic leukemia

AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma

Therapeutic Options for Patients with TP53 Deficient Chronic Lymphocytic Leukemia: Narrative Review

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