Single-Agent Inhibition of Chk1 Is Antiproliferative in Human Cancer Cell Lines In Vitro and Inhibits Tumor Xenograft Growth In Vivo

Davies, Kurtis D.; Humphries, Michael; Sullivan, Francis X.; Carlowitz, Ira von; Huérou, Yvan Le; Mohr, Peter J.; Wang, Bin; Blake, James F.; Lyon, Michael A.; Gunawardana, Indrani; Chicarelli, Mark; Wallace, Eli M.; Größ, Stefan

doi:10.3727/096504011x13079697132961

Cited by 25 publications

(41 citation statements)

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“…Genomic damage resulting from deregulated DNA replication, determined by gH2AX staining in S-phase cells, is not only a hallmark of the response to WEE1 monotherapy (described here) but also both the combination of the WEE1 and CHK1 inhibitors and CHK1 inhibitor monotherapy (42). Our own work supports the in vivo combination benefit from combined WEE1 and CHK1 inhibition (data not shown; ref.…”

Section: Discussionsupporting

confidence: 74%

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Guertin

Liu

et al. 2013

Molecular Cancer Therapeutics

153

142

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Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here, we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We show that MK-1775, a potent and selective ATP-competitive inhibitor of WEE1, is cytotoxic across a broad panel of tumor cell lines and induces DNA double-strand breaks. MK-1775-induced DNA damage occurs without added chemotherapy or radiation in S-phase cells and relies on active DNA replication. At tolerated doses, MK-1775 treatment leads to xenograft tumor growth inhibition or regression. To begin addressing potential response markers for MK-1775 monotherapy, we focused on PKMYT1, a kinase functionally related to WEE1. Knockdown of PKMYT1 lowers the EC 50 of MK-1775 by five-fold but has no effect on the cell-based response to other cytotoxic drugs. In addition, knockdown of PKMYT1 increases markers of DNA damage, gH2AX and pCHK1 S345 , induced by MK-1775. In a post hoc analysis of 305 cell lines treated with MK-1775, we found that expression of PKMYT1 was below average in 73% of the 33 most sensitive cell lines. Our findings provide rationale for WEE1 inhibition as a potent anticancer therapy independent of a genotoxic partner and suggest that low PKMYT1 expression could serve as an enrichment biomarker for MK-1775 sensitivity.

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Section: Discussionsupporting

confidence: 74%

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Guertin

Liu

et al. 2013

Molecular Cancer Therapeutics

153

142

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“…As shown in previous chapters of this thesis and also in previous reports of CHK1i (King et al, 2015, Brooks et al, 2013, Davies et al, 2011b, Walton et al, 2012, only a subset of tumour cell lines is sensitive to CHK1i single-agent treatment and there is significant proportion of tumour cell lines which are not sensitive to singleagent treatment. Here, low-dose hydroxyurea (0.2 mM) was added concurrently with CHK1i to induce replication stress in the melanoma cells and sensitise them to CHK1i inhibition.…”

Section: Discussionsupporting

confidence: 72%

“…Thus, there is a significant portion of melanoma patients who are still in need of effective treatments. CHK1 inhibitor (CHK1i) single-agent treatment was found to be cytotoxic to various melanoma cell lines and other cancer cell lines as reported in previous chapters in this thesis and other reports (King et al, 2015, Brooks et al, 2013, Davies et al, 2011b, Walton et al, 2012. I have found that CHK1i hypersensitivity is associated with defective S phase checkpoint arrest in melanoma cells, and the majority of the CHK1i-hypersensitive cell lines have an uncoupling of checkpoint activation and CDC25A degradation that is largely responsible for the S phase arrest, as discussed in Chapter 3 of this thesis.…”

Section: Introductionsupporting

confidence: 68%

“…CHK1 inhibitor single-agent treatment was demonstrated to be extremely effective in some cancer types including melanoma as reported in this thesis and others (Bryant et al, 2014, Davies et al, 2011b, Brooks et al, 2013.…”

Section: Discussionmentioning

confidence: 55%

“…There have been several reports demonstrating CHK1 inhibitor single-agent sensitivity in cancer cell lines (Bryant et al, 2014, Davies et al, 2011b, although the underlying mechanism and markers of sensitivity for the single-agent activity were not explored. Our lab had previously shown that CHK1 inhibitor single-agent treatment has cytotoxic effect on a significant proportion of melanoma cells (Brooks et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms and markers of CHK1 inhibitors sensitivity in melanoma

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Landscape for the treatment of cancer patients has recently been changed with the arrival of targeted therapies in different malignancies with the drugs targeting specific mutations and genetic alterations such as, EGF-receptor blockers and BRAF inhibitors, and the drugs such as PARP inhibitors which exploit defects in the cancers and cause synthetic lethality. In this thesis, I investigated to understand the mechanism of action of a drug that targets the cell cycle checkpoint regulator, checkpoint kinase 1 (CHK1) and explored its potential therapeutic usage in specific cancer types. Checkpoint kinase 1 inhibitor (CHK1i) as a single-agent treatment is effective in some of the cancer types with high levels of replication stress, including melanoma. However, the mechanism and manner of cell-killings induced by CHK1i single-agent treatment is still poorly understood. To identify the patient population who can benefit from CHK1i single-agent treatment, it is important to understand how single-agent CHK1i induced the cell killing. CHK1i has been investigated in pre-clinical studies and clinical trials, and shown to enhance the efficacy of chemotherapeutic drugs, particularly those that promote replication stress such as gemcitabine.Most of those investigations were based on the previous notion that CHK1i abrogates the G2/M phase checkpoint to cause mitotic catastrophe and results in cancer cell death. However, considering numerous roles of CHK1 playing in cell cycle and DNA damage response pathway, this mechanism alone may not represent the entirety of sensitivity to CHK1i. CHK1 has different roles in S and G2/M phases of cell cycle such as controlling the G2/M checkpoint, stabilising the stalled replication fork, and inhibiting the apoptosis together with other DNA damage repair and cell cycle checkpoint regulators. When one of these other regulators/pathways has defects, inhibiting CHK1 can be synthetically lethal to the cancer cells. Another CHK1 function in S phase is regulating CDC25A; CHK1 triggers the destabilisation of CDC25A upon DNA damage and replication stress.The normal role of CDC25A in S phase progression is activation of CDK2 which is required for progression into and through S phase. CDC25A dysregulation and overexpression has been reported in various cancers and shown to create increased replication stress in the cells. Tumours with high level of replication stress have been suggested to be selectively susceptible to the inhibition of CHK1 and its upstream regulator, ATR.In this thesis, it was firstly shown that S phase cell cycle checkpoint defect is a common feature of CHK1i-hypersensitive melanoma cell lines, and this defect is often associated with failure to degrade CDC25A in response to replication stress. Furthermore, CDC25A over-expression and/or dysregulation contributes to CHK1i sensitivity in hypersensitive melanoma cell lines. Secondly, it was demonstrated that CHK1i induced high level of replication stress via RPA hyperphosphorylation and subsequently RPA depletion occurred in h...

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Personalised Medicine: Genome Maintenance Lessons Learned from Studies in Yeast as a Model Organism

Abugable

Awwad

Fleifel

et al. 2017

Advances in Experimental Medicine and Biology

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Yeast research has been tremendously contributing to the understanding of a variety of molecular pathways due to the ease of its genetic manipulation, fast doubling time as well as being cost-effective. The understanding of these pathways did not only help scientists learn more about the cellular functions but also assisted in deciphering the genetic and cellular defects behind multiple diseases. Hence, yeast research not only opened the doors for transforming basic research into applied research, but also paved the roads for improving diagnosis and innovating personalized therapy of different diseases. In this chapter, we discuss how yeast research has contributed to understanding major genome maintenance pathways such as the S-phase checkpoint activation pathways, repair via homologous recombination and non-homologous end joining as well as topoisomerases-induced protein linked DNA breaks repair. Defects in these pathways lead to neurodegenerative diseases and cancer. Thus, the understanding of the exact genetic defects underlying these diseases allowed the development of personalized medicine, improving the diagnosis and treatment and overcoming the detriments of current conventional therapies such as the side effects, toxicity as well as drug resistance.

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Single-Agent Inhibition of Chk1 Is Antiproliferative in Human Cancer Cell Lines In Vitro and Inhibits Tumor Xenograft Growth In Vivo

Cited by 25 publications

References 0 publications

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Mechanisms and markers of CHK1 inhibitors sensitivity in melanoma

Personalised Medicine: Genome Maintenance Lessons Learned from Studies in Yeast as a Model Organism

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