Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer

Stephenson, Joe; Nemunaitis, John; Joy, Anil A.; Martin, Julie; Jou, Ying‐Ming; Zhang, Da; Statkevich, Paul; Yao, Siu-Long; Zhu, Yali; Zhou, Honghong; Small, Karen; Bannerji, Rajat; Edelman, Martin J.

doi:10.1016/j.lungcan.2013.11.020

Cited by 88 publications

(64 citation statements)

References 12 publications

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“…Although clinical trials showed that dinaciclib displayed tolerable toxicity (Parry et al, 2010;Nemunaitis et al, 2013;Fabre et al, 2014;Asghar et al, 2015;Kumar et al, 2015), some reports of randomized phase 2 trials of dinaciclib have been disappointing (Mita et al, 2014) with no significant response, particularly in patients with non-small cell lung cancer (Stephenson et al, 2014) or acute lymphoblastic leukemia (Gojo et al, 2013). In this study, we showed that neither ABT-737 nor dinaciclib is a potent cytotoxic agent when used alone and that efficacy was poor at the clinically achievable range.…”

Section: Discussionmentioning

confidence: 51%

“…Parry et al (2010) also showed that dinaciclib inhibited cell proliferation and cell-cycle progression in multiple tumor cell lines across a broad range of tumor types with different genetic backgrounds and induced regression of established solid tumors in mouse models. Despite research advances, reports of randomized phase 2 trials of dinaciclib in solid tumors have been disappointing (Mita et al, 2014), with no significant response in patients with non-small cell lung cancer (Stephenson et al, 2014) or acute lymphoblastic leukemia (Gojo et al, 2013). In this study, we investigated the cellular responses to CDK inhibitors in a panel of glioma cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Jane

Premkumar

Cavaleri

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell-cycle control, there is a strong rationale for examining the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72-hour 3-[4,5-dimethylthiazol-2yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium (MTS) assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed, but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth-signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitors ABT-263-nitrophenyl]sulfonylbenzamide) with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential; the release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor; phosphatidylserine exposure on the plasma membrane surface and activation of caspases and poly ADP-ribose polymerase. Mechanistic studies revealed that dinaciclib promoted proteasomal degradation of Mcl-1. These observations may have important clinical implications for the design of experimental treatment protocols for malignant human glioma.

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Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Jane

Premkumar

Cavaleri

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…4), and the CDK1/2/5/9 inhibitor, dinaciclib (MK-7965, formerly SCH-727965; refs. 18,19). On the basis of the frequent finding of aberrations in the cell-cycle pathway across diverse malignancies, prosecution of this pathway in multiple tumor types merits further exploration.…”

Section: Discussionmentioning

confidence: 99%

“…With novel promising CDK inhibitors in clinical trials (4,(16)(17)(18)(19), the comprehensive analysis of cell-cycle gene aberrations among diverse cancer types is of interest. Next-generation sequencing (NGS) technology makes rapid and accurate identification of these aberrations feasible.…”

Section: Introductionmentioning

confidence: 99%

Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics

Helsten

Kato

Schwaederlé

et al. 2016

Molecular Cancer Therapeutics

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Alterations in the cyclin-dependent kinase (CDK)-retinoblastoma (RB) machinery disrupt cell-cycle regulation and are being targeted in drug development. To understand the cancer types impacted by this pathway, we analyzed frequency of abnormalities in key cell-cycle genes across 4,864 tumors using nextgeneration sequencing (182 or 236 genes; Clinical Laboratory Improvement Amendments laboratory). Aberrations in the cellcycle pathway were identified in 39% of cancers, making this pathway one of the most commonly altered in cancer.

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“…In phase I clinical trials, Dianciclib demonstrated promising results: stable disease in different cancer types with tolerable toxicity profiles. However, the results from randomised Phase II trials with advanced breast cancer and non-small cell lung cancers were disappointing (Mita et al, 2014, Stephenson et al, 2014. Recently new generation of more selective CDK4/6 inhibitors, such as Abemaciclib, Palbociclib and Ribociclib, showed promising antitumour acitivity with manageable toxicity and currently in phase III trials.…”

Section: Mismatch Repair (Mmr)mentioning

confidence: 99%

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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Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer

Cited by 88 publications

References 12 publications

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted Therapeutics

Mechanisms and markers of CHK1 inhibitors sensitivity in melanoma

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