|
| Status |
Public on Jul 01, 2023 |
| Title |
Palbociclib interferes with origin firing in a pRb independent manner |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by genome tiling array
|
| Summary |
Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here for the first time how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patient
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| |
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| Overall design |
nascent-DNA from early S-phase versus nascent-DNA from late S-phase
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| |
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| Contributor(s) |
Kim S, Koudrioukoff S, Jean-Charles Cadoret CM |
| Citation missing |
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| Submission date |
Jul 21, 2021 |
| Last update date |
Jul 03, 2023 |
| Contact name |
Jean-Charles Cadoret |
| E-mail(s) |
jean-charles.cadoret@ijm.fr
|
| Organization name |
CNRS/ Université de Paris
|
| Street address |
15 rue hélène Brion
|
| City |
Paris |
| ZIP/Postal code |
75013 |
| Country |
France |
| |
|
| Platforms (1) |
| GPL10123 |
Agilent-022060 SurePrint G3 Human CGH Microarray 4x180K (Feature Number version) |
|
| Samples (10)
|
| GSM5464401 |
NCI treated with Ribociclib replicate 2 |
| GSM5464402 |
NCI treated with Palbociclib replicate 1 |
| GSM5464403 |
NCI treated with Palbociclib replicate 2 |
| GSM5464404 |
MDA-MB-438 treated with DMSO replicate 1 |
| GSM5464405 |
MDA-MB-438 treated with DMSO replicate 2 |
| GSM5464406 |
MDA-MB-438 treated with Palbociclib replicate 1 |
| GSM5464407 |
MDA-MB-438 treated with Palbociclib replicate 2 |
|
| Relations |
| BioProject |
PRJNA748597 |
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