Abstract:
:As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.
journal_name
Mol Oncoljournal_title
Molecular oncologyauthors
Drápela S,Khirsariya P,van Weerden WM,Fedr R,Suchánková T,Búzová D,Červený J,Hampl A,Puhr M,Watson WR,Culig Z,Krejčí L,Paruch K,Souček Kdoi
10.1002/1878-0261.12756subject
Has Abstractpub_date
2020-10-01 00:00:00pages
2487-2503issue
10eissn
1574-7891issn
1878-0261journal_volume
14pub_type
杂志文章abstract::DNA ploidy analysis is useful for prognostication in cancer patients, but the genomic details underlying ploidy changes are not fully understood. To improve this understanding, we compared DNA ploidy status with karyotypic and comparative genomic hybridization data on 51 endometrial adenocarcinomas. Out of 34 DNA dipl...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2011.10.002
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abstract::Breast cancer is a heterogeneous disease that can be divided in subtypes based on histology, gene expression profiles as well as differences in genomic aberrations. Distinct global DNA methylation profiles have been reported in normal breast epithelial cells as well as in breast tumors. However, the influence of the t...
journal_title:Molecular oncology
pub_type: 杂志文章
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journal_title:Molecular oncology
pub_type: 杂志文章
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更新日期:2014-12-01 00:00:00
abstract::Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of pro...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12365
更新日期:2018-10-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12810
更新日期:2020-12-01 00:00:00
abstract::Although mutations in the phosphoinositide 3-kinase catalytic subunit (PIK3CA) are common in breast cancer, PI3K inhibitors alone have shown modest efficacy. We sought to identify additional pathways altered in PIK3CA-mutant tumors that might be targeted in combination with PI3K inhibitors. We generated two transgenic...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12053
更新日期:2017-05-01 00:00:00
abstract:PURPOSE:To compare the distribution and prognostic effect of the breast cancer molecular subtypes in young and elderly breast cancer patients. PATIENTS AND METHODS:Our study population (n = 822) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. A total of...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.03.022
更新日期:2014-07-01 00:00:00
abstract::Triple-negative breast cancer (TNBC) liver metastasis is associated with poor prognosis and low patient survival. It occurs when tumor cells disseminate from primary tumors, circulate in blood/lymph [circulating tumor cells (CTCs)], and acquire distinct characteristics during disease progression toward the metastatic ...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12533
更新日期:2019-09-01 00:00:00
abstract::The elevated expression and activation of human telomerase reverse transcriptase (hTERT) is associated with the unlimited proliferation of cancer cells. However, the excise mechanism of hTERT regulation during carcinogenesis is not well understood. In this study, we discovered cleavage and polyadenylation specific fac...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.02.001
更新日期:2014-05-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2012.10.006
更新日期:2012-12-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2015.12.005
更新日期:2016-03-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2014.08.013
更新日期:2015-01-01 00:00:00
abstract:INTRODUCTION:Most analyses of high throughput cancer data represent tumors by "atomistic" single-gene properties. Pathifier, a recently introduced method, characterizes a tumor in terms of "coarse grained" pathway-based variables. METHODS:We applied Pathifier to study a very large dataset of 2000 breast cancer samples...
journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2015.04.006
更新日期:2015-08-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.10.011
更新日期:2015-03-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12748
更新日期:2020-08-01 00:00:00
abstract::The above article, published online on 28 February 2020 in Wiley Online Library (wileyonlinelibrary.com) as an Accepted Article (https://doi.org/10.1002/1878-0261.12656), has been withdrawn at the authors' request, and in agreement between the authors, the journal Editors in Chief J. E. Celis and K. Ryan, and John Wil...
journal_title:Molecular oncology
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更新日期:2020-12-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2011.12.001
更新日期:2012-06-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12785
更新日期:2020-11-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2010.06.005
更新日期:2010-10-01 00:00:00
abstract::Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional fac...
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doi:10.1002/1878-0261.12878
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.04.004
更新日期:2014-10-01 00:00:00
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pub_type: 杂志文章
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更新日期:2017-10-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12871
更新日期:2020-12-02 00:00:00
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journal_title:Molecular oncology
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doi:10.1002/1878-0261.12507
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1016/j.molonc.2015.10.014
更新日期:2015-12-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
doi:10.1002/1878-0261.12096
更新日期:2017-07-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2013.05.002
更新日期:2013-10-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2014.09.010
更新日期:2015-02-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2015.03.009
更新日期:2015-08-01 00:00:00