Exploiting DNA mismatch repair deficiency as a therapeutic strategy

Guillotin, Delphine; Martin, Sarah A.

doi:10.1016/j.yexcr.2014.07.004

Cited by 55 publications

(40 citation statements)

References 36 publications

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“…This is one reason that different tumor types show tendencies to respond better to one particular class of DNA-damaging agent. Tumors generally possess inactivating mutations in genes involved in one or more DNA repair pathways resulting in resistance to some classes of agents and sensitivity to others (32)(33)(34). Because of the lack of deep understanding of predicting drug sensitivity, the discovery of novel agents helps to increase the number of responsive indications.…”

Section: Discussionmentioning

confidence: 99%

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

King

Diaz

McNeely

et al. 2015

Molecular Cancer Therapeutics

155

175

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CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

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Section: Discussionmentioning

confidence: 99%

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

King

Diaz

McNeely

et al. 2015

Molecular Cancer Therapeutics

155

175

View full text Add to dashboard Cite

show abstract

“…This approach has proven successful in the clinic for BRCA1/2 mutated cancers that are synthetic lethal with PARP inhibitors (Tutt et al , ). Progress is being made in identifying synthetic lethal interactions with MMR and drugs that induce oxidative DNA damage may be a promising therapeutic strategy (Guillotin & Martin, ). Across many different solid tumours types, drugs that are synthetic lethal in MMR‐deficient cells include methotrexate and cytarabine (Martin et al , ; Hewish et al , ) and increased sensitivity to cytarabine and other nucleoside analogues, including clofarabine and fludarabine, has also been shown in AML and lymphoblastoid cells (Fordham et al , ).…”

Section: Dna Repairmentioning

confidence: 99%

Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia

Irving

2015

Br J Haematol

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Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse.

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“…There is an ongoing research aiming to develop synthetic lethal strategy for the targeting of MSI-H cancers [140]. …”

Section: Introductionmentioning

confidence: 99%

Cytotoxic and targeted therapy for hereditary cancers

Iyevleva

Imyanitov

2016

Hered Cancer Clin Pract

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There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning.

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Exploiting DNA mismatch repair deficiency as a therapeutic strategy

Cited by 55 publications

References 36 publications

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia

Cytotoxic and targeted therapy for hereditary cancers

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