Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Lin, Aimee Bence; McNeely, Samuel C.; Beckmann, Richard P.

doi:10.1158/1078-0432.ccr-16-0083

Cited by 75 publications

(71 citation statements)

References 90 publications

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“…Defect in DDR related genes in tumor cells leads to impaired DNA repair, triggering apoptosis in tumor cells. Recent studies have demonstrated that DDR is important for the maintenance of tumor genome integrity, and dysregulation of DDR sensitizes tumor cells to chemotherapy [45][46][47][48]. Thus, inhibition of DDR pathway including HR and NHEJ via chemotherapeutic compounds selectively kill tumor cells that evolve to escape DDR and checkpoint signaling.…”

Section: Discussionmentioning

confidence: 99%

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.

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Section: Discussionmentioning

confidence: 99%

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Wang

et al. 2018

Cell Physiol Biochem

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“…The phase 1 trial conducted in non‐Japanese patients observed tumor shrinkage in 10 of 34 patients, with many of these cases occurring in SCC . Squamous cell carcinoma may harbor increased levels of replication stress and/or DNA damage response, which may contribute to an increased response to CHK1/2 inhibitors . On the basis of these findings, cohorts in SCC are being evaluated in the dose‐expansion phase of the phase 1 study in non‐Japanese patients …”

Section: Discussionmentioning

confidence: 94%

“…Checkpoint kinase 1 (CHK1) is a multifunctional serine/threonine‐specific protein kinase that has a critical role in regulating response to DNA damage . The proteins ataxia telangiectasia mutated and RAD3‐related (ATR) and/or ataxia telangiectasia mutated (ATM) are activated in response to DNA damage, which in turn phosphorylate CHK1 and checkpoint kinase 2 (CHK2), respectively . p53 is another critical mediator of the response to DNA damage.…”

Section: Introductionmentioning

confidence: 99%

“…p53 is another critical mediator of the response to DNA damage. It is activated through phosphorylation by CHK2 and ATM, and participates in a parallel pathway to ATR and CHK1 . CHK1 can also regulate DNA replication checkpoints by maintaining or enhancing the inhibitory phosphorylation of cyclin‐dependent kinases, which are key drivers of cell cycle progression .…”

Section: Introductionmentioning

confidence: 99%

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Dose‐finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors

et al. 2018

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Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single‐arm open‐label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m2 and the global‐recommended dose based on a US study of 105 mg/m2, administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose‐limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose‐limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment‐emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony‐stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose‐independent and time‐independent behavior across both dose levels, similar to the profile observed in the US‐based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.

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“…This cell division consists of interphase and mitosis and is strictly regulated. The cell cycle checkpoint has become a therapeutic target because it is often dysregulated in cancer cells . Previous studies showed that arginine depletion could inhibit cell proliferation in human HCC and melanoma by cell cycle arrest .…”

Section: Discussionmentioning

confidence: 99%

Recombinant human arginase induces apoptosis through oxidative stress and cell cycle arrest in small cell lung cancer

Lam

Cheng³

et al. 2018

Cancer Science

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Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer cases. Small cell lung cancer is characterized by frequent relapse, and current treatments lack tumor specificity. Arginine is a non‐essential amino acid for human normal cells but critical to some tumor cells that cannot synthesize arginine. Therefore, arginine deprivation has become a potential therapeutic option for selected tumors. BCT‐100 is a pegylated arginase that has documented anticancer activity in arginine auxotrophic tumors, such as melanoma, hepatocellular carcinoma, and acute myeloid leukemia. One of the resistance mechanisms to arginase treatment is overexpression of argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC), two important enzymes in the urea cycle. We selected 9 SCLC and 1 non‐small cell lung carcinoma cell lines to determine the growth inhibition effects of BCT‐100 and established that cell lines with low expression of ASS1 and OTC are relatively sensitive to BCT‐100 treatment. Knocking down OTC in a H841 cell line could potentiate its sensitivity to BCT‐100 treatment. Arginine concentration was sharply decreased, accompanied by apoptosis through oxidative stress as well as G1 cell cycle arrest. In addition, BCT‐100 showed an anticancer effect on H446 and H510A xenograft models by lowering arginine levels and inducing apoptosis.

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Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

Cited by 75 publications

References 90 publications

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Dose‐finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors

Recombinant human arginase induces apoptosis through oxidative stress and cell cycle arrest in small cell lung cancer

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