CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal

Crozier, Lisa; Foy, Reece; Mouery, Brandon L.; Whitaker, Robert H.; Corno, Andrea; Spanos, Christos; Ly, Tony; Cook, Jeanette Gowen; Saurin, Adrian T.

doi:10.1101/2021.02.03.428245

Cited by 15 publications

(52 citation statements)

References 91 publications

(110 reference statements)

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“…The Saurin and Demaria groups set out with differing initial goals: Crozier et al (2022) focussed on identifying the mechanisms by which treatment with Cdk4/6 inhibitors (Cdk4/6i) promoted entry into senescence, while Wang et al (2022) aimed to characterise the downstream impact of senescence induction by Cdk4/6i. Both laboratories found that treating non‐cancer cells for a prolonged period of time (i.e.…”

Section: Figure Long‐term Cdk4/6i Treatment Causes Cells To Enter Int...mentioning

confidence: 99%

“…Knocking out p53 allowed cells to re‐enter the cell cycle after Cdk4/6i removal. Using live single‐cell imaging, the Saurin laboratory showed that in the presence of p53, cells after Cdk4/6i washout either remain in G0/G1 or re‐enter S‐phase, complete DNA replication and arrest in the subsequent G2, where they withdraw from the cell cycle (Crozier et al, 2022). In either phase, arrest requires p53.…”

Section: Figure Long‐term Cdk4/6i Treatment Causes Cells To Enter Int...mentioning

confidence: 99%

“…Having elucidated these pathways in non‐transformed cells, the Saurin laboratory moved on to cancer cells and determined that MCF7 exhibited a similar downregulation of replisome components during arrest with Cdk4/6i. Examining a panel of p53 wild‐type and p53‐null cancer cell lines, Crozier et al (2022) showed that although G0/G1 arrest in the presence of Cdk4/6i was, on average, less complete in cancer cells than in non‐transformed cells, replication stress‐related DNA damage was still increased after Cdk4/6i washout, indicating that a complete G0/G1 arrest is not an absolute prerequisite. In fact, p53‐null cancer cells also accumulated DNA damage during Cdk4/6i treatment due to incomplete inhibition of cell proliferation generating replication stress.…”

Section: Figure Long‐term Cdk4/6i Treatment Causes Cells To Enter Int...mentioning

confidence: 99%

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Cells on lockdown: long‐term consequences of CDK4/6 inhibition

Barr

McClelland

2022

The EMBO Journal

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Inhibition of cyclin‐dependent kinases Cdk4/6 is emerging as a useful anti‐proliferative chemotherapy, but it remains unclear how durable inhibition of cancer cell proliferation is achieved to promote a long‐lasting response in patients, or how toxicity is limited to cancer cells with minimal side effects. Two recent papers in The EMBO Journal investigating senescence induction following prolonged Cdk4/6 inhibitor treatment now reveal important insights into ways to increase anti‐tumour effects of Cdk4/6 inhibition and to reduce therapy‐induced side effects of senescence induction.

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Section: Figure Long‐term Cdk4/6i Treatment Causes Cells To Enter Int...mentioning

confidence: 99%

Section: Figure Long‐term Cdk4/6i Treatment Causes Cells To Enter Int...mentioning

confidence: 99%

Section: Figure Long‐term Cdk4/6i Treatment Causes Cells To Enter Int...mentioning

confidence: 99%

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Cells on lockdown: long‐term consequences of CDK4/6 inhibition

Barr

McClelland

2022

The EMBO Journal

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“…Quantification of DNA content by Hoechst sum intensity allows the gating of cells into G1, S and G2/M phases (electronic supplementary material, figure S2b) [15]. P-Rb is bimodally distributed in a population of asynchronously cycling cells, reflecting the proliferation status of the population with G0 cells (and palbociclib-arrested cells) displaying hypophosphorylated Rb [52][53][54] (electronic supplementary material, figure S2c).…”

Section: P21 and P27 Are Not Required For Entry Into G1 Arrest With Palbociclib In Rpe1 Cellsmentioning

confidence: 99%

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Pennycook

Barr

2021

Open Biol.

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The use of CDK4/6 inhibitors in the treatment of a wide range of cancers is an area of ongoing investigation. Despite their increasing clinical use, there is limited understanding of the determinants of sensitivity and resistance to these drugs. Recent data have cast doubt on how CDK4/6 inhibitors arrest proliferation, provoking renewed interest in the role(s) of CDK4/6 in driving cell proliferation. As the use of CDK4/6 inhibitors in cancer therapies becomes more prominent, an understanding of their effect on the cell cycle becomes more urgent. Here, we investigate the mechanism of action of CDK4/6 inhibitors in promoting cell cycle arrest. Two main models explain how CDK4/6 inhibitors cause G1 cell cycle arrest, which differ in their dependence on the CDK inhibitor proteins p21 and p27. We have used live and fixed single-cell quantitative imaging, with inducible degradation systems, to address the roles of p21 and p27 in the mechanism of action of CDK4/6 inhibitors. We find that CDK4/6 inhibitors can initiate and maintain a cell cycle arrest without p21 or p27. This work clarifies our current understanding of the mechanism of action of CDK4/6 inhibitors and has implications for cancer treatment and patient stratification.

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“…When transcribed, these two viral proteins deregulate the cell cycle and impede genomic stability in the host cell by rendering several putative tumor suppressors inactive, including tumor protein 53 (p53) and retinoblastoma (Rb) (6,7). In addition, activation of cyclin-dependent kinase (CDK)-4 and -6 induces replication stress in the cervical epithelium and promotes mitotic entry despite DNA damage (6,(8)(9)(10)(11)(12). The p16 CDK inhibitor 2A (CDKN2A) protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle and regulates the DNA damage response (8).…”

Section: Introductionmentioning

confidence: 99%

Integrative meta‑analysis of gene expression profiles identifies FEN1 and ENDOU as potential diagnostic biomarkers for cervical squamous cell carcinoma

et al. 2021

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Cervical carcinoma is a global public health burden. Given that it is usually asymptomatic at potentially curative stages, the development of clinically accurate tests is critical for early detection and individual risk stratification. The present study performed an integrative meta-analysis of the transcriptomes from 10 cervical carcinoma cohorts, with the aim of identifying biomarkers that are associated with malignant transformation of cervical epithelium, and establish their clinical applicability. From among the top ranked differentially expressed genes, flap structure-specific endonuclease 1 (FEN1) and poly (U)-specific endoribonuclease (ENDOU) were selected for further validation, and their clinical applicability was assessed using immunohistochemically stained microarrays comprising 110 tissue cores, using p16 and Ki67 staining as the comparator tests. The results demonstrated that FEN1 expression was significantly upregulated in 65% of tumor specimens (P=0.0001), with no detectable expression in the non-tumor tissues. Furthermore, its expression was significantly associated with Ki67 staining in tumor samples (P<0.0001), but no association was observed with p16 expression or the presence of human papilloma virus types 16/18, patient age, tumor grade or stage. FEN1 staining demonstrated lower sensitivity than p16 (69.3 vs. 96.8%) and Ki67 (69.3 vs. 76.3%); however, the specificity was identical to p16 and higher than that of Ki67 (100 vs. 71.4%). ENDOU staining was consistent with the microarray results, demonstrating 1% positivity in tumors and 40% positivity in non-tumor tissues. Gene set enrichment analysis of cervical tumors overexpressing FEN1 revealed its association with enhanced growth factor signaling, immune response inhibition and extracellular matrix remodeling, whereas tumors with low ENDOU expression exhibited inhibition of epithelial development and differentiation processes. Taken together, the results of the present study demonstrate the feasibility of the integrative meta-analysis approach to identify relevant biomarkers associated with cervical carcinogenesis. Thus, FEN1 and ENDOU may be useful diagnostic biomarkers for squamous cervical carcinoma. However, further studies are required to determine their diagnostic performance in larger patient cohorts and validate the results presented here.

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CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal

Cited by 15 publications

References 91 publications

Cells on lockdown: long‐term consequences of CDK4/6 inhibition

Cells on lockdown: long‐term consequences of CDK4/6 inhibition

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Integrative meta‑analysis of gene expression profiles identifies FEN1 and ENDOU as potential diagnostic biomarkers for cervical squamous cell carcinoma

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