A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Montagnoli, Alessia; Valsasina, Barbara; Croci, Valter; Menichincheri, Maria; Rainoldi, Sonia; Marchesi, Vanessa; Tibolla, Marcellino; Tenca, Pierluigi; Brotherton, Deborah; Albanese, Clara; Patton, Veronica; Alzani, Rachele; Ciavolella, Antonella; Sola, Francesco; Molinari, Agnese; Volpi, Daniele; Avanzi, Nilla; Fiorentini, Francesco; Cattoni, Marina; Healy, Sandra; Ballinari, Dario; Pesenti, Enrico; Isacchi, Antonella; Moll, Jürgen; Bensimon, Aaron; Vanotti, Ermes; Santocanale, Corrado

doi:10.1038/nchembio.90

Cited by 186 publications

(210 citation statements)

References 47 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…We found no correlation between the anti-proliferative response to CDK9 inhibition and p53 expression or mutational status (Supplemental Fig. 4A,B), consistent with previous findings indicating that PHA-767491 inhibits cancer cell proliferation through p53-independent mechanisms (Montagnoli et al 2008).…”

Section: Myc Expression Predicts Response To Cdk9 Inhibitionsupporting

confidence: 80%

“…Treatment with PHA-767491 (50 mg/kg, twice per day, 5 d per week) or vehicle was initiated upon detection of bioluminescence. Consistent with previous findings (Montagnoli et al 2008), PHA-767491 treatment was well tolerated in mice (Supplemental 7E) and triggered a decrease in Pol II Ser2 phosphorylation in the emerging tumors (Fig. 7G).…”

Section: Cdk9 Is Required For Initiation and Maintenance Of Myc-overesupporting

confidence: 79%

“…After testing four different CDK9 inhibitors (Supplemental Fig. 3A; Wang and Fischer 2008), we found that PHA-767491, a dual CDK9 and CDC7 (cell division cycle 7) kinase inhibitor (Montagnoli et al 2008), most closely recapitulated shRNA-mediated CDK9 inhibition in both human and murine cell lines ( Fig. 3A-C; Supplemental Fig.…”

Section: Pharmacological Inhibition Of Cdk9 In Hcc Cell Linesmentioning

confidence: 99%

See 2 more Smart Citations

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

et al. 2014

View full text Add to dashboard Cite

One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.

show abstract

Section: Myc Expression Predicts Response To Cdk9 Inhibitionsupporting

confidence: 80%

Section: Cdk9 Is Required For Initiation and Maintenance Of Myc-overesupporting

confidence: 79%

Section: Pharmacological Inhibition Of Cdk9 In Hcc Cell Linesmentioning

confidence: 99%

See 1 more Smart Citation

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Although Cdc7 depletion does not change fork progression rates (Fig. 1), and Cdc7 inhibition even increased fork rates (37), it does result in delayed S phase progression, accumulation of DNA damage, and, in tumor cells, cell death, suggesting that reduced origin firing also leads to difficulties with completing replication (38).…”

Section: Discussionmentioning

confidence: 99%

Chk1 promotes replication fork progression by controlling replication initiation

Petermann

Woodcock

Helleday

2010

Proc. Natl. Acad. Sci. U.S.A.

251

243

View full text Add to dashboard Cite

DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.

show abstract

“…This would translate into low therapeutic indices often found for conventional chemotherapeutic drugs targeting the cell cycle. However, potent cancer cell-specific killing has been demonstrated in preclinical models after inhibition of origin licensing [125] or, alternatively, origin activation through targeting Cdc7 kinase [111,118,126,127]. Tumour cell specificity is thought to result from transformed cells entering S phase with inadequate numbers of competent origins to complete chromosomal replication.…”

Section: The Dna Replication Initiation Machinery-a Promising Anti-camentioning

confidence: 99%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

531

385

View full text Add to dashboard Cite

Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

show abstract

A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Cited by 186 publications

References 47 publications

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

Chk1 promotes replication fork progression by controlling replication initiation

The cell cycle and cancer

Contact Info

Product

Resources

About