Enhancing CHK1 inhibitor lethality in glioblastoma

Tang, Yong; Dai, Yun; Grant, Steven; Dent, Paul

doi:10.4161/cbt.19240

Cited by 39 publications

(35 citation statements)

References 44 publications

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“…Pharmacodynamic analyses of intratumoral MAPK, PI3K and mTOR signaling were not completed leaving the cause of the lack of efficacy unresolved (46-48). Other agents, possibly those directly inhibiting Raf[mgn]MEK[mgn]Erk signal cascades, such as the MEK inhibitor AZD6244, may also curtail ON123300-induced Erk activation (49, 50); however with the gefitinib-ON123300 combination not only was Erk activation suppressed Akt inhibition was enhanced.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Zhang

Zhou

et al. 2014

Molecular Cancer Therapeutics

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ON123300 is a low molecular weight multi-kinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochemical assays indicated ON123300 was a strong inhibitor of Ark5 and CDK4 as well as growth factor receptor tyrosine kinases such as Beta-type platelet-derived growth factor receptor [PDGFRβ]. ON123300 inhibited U87 glioma cell proliferation with an IC50 = 3.4 ± 0.1 μM and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation; both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K initiated PI3K negative feedback loop. Co-treatment with the EGFR inhibitor gefitinib [GFN] produced synergistic cytotoxic effects. Pursuant to the in vitro studies, in vivo pharmacokinetic [PK] and pharmacodynamic [PD] studies of ON123300 were completed in mice bearing intracerebral U87 tumors following IV doses of 5 mg/kg and 25 mg/kg alone, and also at the higher dose concurrently with GFN. ON123300 showed high brain and brain tumor accumulation based on brain partition coefficient values of at least 2.5. Consistent with the in vitro studies, single agent ON123300 caused a dose-dependent suppression of phosphorylation of Akt as well as activation of Erk in brain tumors, whereas addition of GFN to the ON123300 regimen significantly enhanced p-Akt inhibition and prevented Erk activation. In summary, ON123300 demonstrated favorable PK characteristics and future development for brain tumor therapy would require use of combinations, such as GFN, that mitigated its Erk activation and enhanced its activity.

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Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Zhang

Zhou

et al. 2014

Molecular Cancer Therapeutics

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“…Inactivation of CHK1 or CHK2 has also been reported to induce sensitization to other agents, including inhibitors of mitogen-activated protein kinase 1/2 (MAPK1/2) (e.g., PD184352 or selumetinib), 286 SRC family kinases, 287 or WEE1 (e.g., MK-1775), 190,288-291 as well as antimitotics (e.g., monastrol or sagopilone) 292,293 ( Table 1 ).…”

Section: Preclinical Evaluation Of Atm Chk2 Atr or Chk1 Inhibitorsmentioning

confidence: 99%

Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy

Manic¹,

Obrist

Sistigu³

et al. 2015

Molecular & Cellular Oncology

125

124

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The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of processes crucial for the preservation of genomic stability that act as a barrier against tumorigenesis and tumor progression. Mutations and/or deletions of ATM and/or CHK2 are frequently found in tumors and predispose to cancer development. In contrast, the ATR–CHK1 pathway is often upregulated in neoplasms and is believed to promote tumor growth, although some evidence indicates that ATR and CHK1 may also behave as haploinsufficient oncosuppressors, at least in a specific genetic background. Inactivation of the ATM–CHK2 and ATR–CHK1 pathways efficiently sensitizes malignant cells to radiotherapy and chemotherapy. Moreover, ATR and CHK1 inhibitors selectively kill tumor cells that present high levels of replication stress, have a deficiency in p53 (or other DDR players), or upregulate the ATR–CHK1 module. Despite promising preclinical results, the clinical activity of ATM, ATR, CHK1, and CHK2 inhibitors, alone or in combination with other therapeutics, has not yet been fully demonstrated. In this Trial Watch, we give an overview of the roles of the ATM-CHK2 and ATR-CHK1 pathways in cancer initiation and progression, and summarize the results of clinical studies aimed at assessing the safety and therapeutic profile of regimens based on inhibitors of ATR and CHK1, the only 2 classes of compounds that have so far entered clinics.

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“…Enhancing radioresponsiveness of tumors by using checkpoint kinase inhibitors is theoretically a promising approach to increase efficacy of radiotherapy (29). Thus, several studies have analyzed the effects of combined applications of checkpoint kinase inhibitors and ionizing radiation (30)(31)(32)(33). Nevertheless, the enhancement of radioresponsiveness of CCA cells by checkpoint kinase inhibitors has not been investigated.…”

Section: Association Between Cellular Radiosensitivity and G1/g2 Checmentioning

confidence: 99%

Association between cellular radiosensitivity and G1/G2 checkpoint proficiencies in human cholangiocarcinoma cell lines

Hematulin

Sagan²,

Sawanyawisuth

et al. 2014

International Journal of Oncology

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Cholangiocarcinoma is a destructive malignancy with a poor prognosis and lack of effective medical treatment. Radiotherapy is an alternative treatment for patients with unresectable cholangiocarcinoma. However, there are limited data on the radiation responsiveness of individual cholangiocarcinoma cells, which is a key factor that influences radiation treatment outcome. In this study, we found that cholangiocarcinoma cell lines differ remarkably in their radiosensitivity. The variation of radiosensitivity of cholangiocarcinoma cells correlates with their p53 status and existing G1 and/or G2 checkpoint defects. We also demonstrated the potential of checkpoint kinase Chk1/2 inhibition on the enhancement of the radiosensitivity of cholangiocarcinoma cells. Thus, this study provides useful information for predicting radiation response and provides evidence for the enchantment of radiotherapeutic efficiency by targeting checkpoint kinase Chk1/2 in some subpopulations of cholangiocarcinoma patients.

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Enhancing CHK1 inhibitor lethality in glioblastoma

Cited by 39 publications

References 44 publications

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Trial Watch: Targeting ATM–CHK2 and ATR–CHK1 pathways for anticancer therapy

Association between cellular radiosensitivity and G1/G2 checkpoint proficiencies in human cholangiocarcinoma cell lines

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