CHK1 inhibition exacerbates replication stress induced by IGF blockade

We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. Aimin...

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Vydáno v:Oncogene Ročník 41; číslo 4; s. 476 - 488
Hlavní autoři: Wu, Xiaoning, Seraia, Elena, Hatch, Stephanie B., Wan, Xiao, Ebner, Daniel V., Aroldi, Francesca, Jiang, Yanyan, Ryan, Anderson J., Bogenrieder, Thomas, Weyer-Czernilofsky, Ulrike, Rieunier, Guillaume, Macaulay, Valentine M.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 21.01.2022
Nature Publishing Group
Témata:
13/31
14
14/19
631/1647/2163
631/67/1059/602
96/1
96/106
96/109
96/47
96/98
Apoptosis
Breast cancer
Cell Biology
Cell culture
Cell death
Cell Line, Tumor
Cell survival
Cell viability
Checkpoint Kinase 1 - antagonists & inhibitors
CHK1 protein
DNA biosynthesis
Enzyme inhibitors
High-Throughput Screening Assays - methods
Human Genetics
Humans
Insulin
Insulin-like growth factors
Internal Medicine
Lethality
Medicine
Medicine & Public Health
Oncology
Phenotypes
Receptor, IGF Type 1 - metabolism
Replication
Single-stranded DNA
Transfection
Tumor cell lines
Tumors
ISSN:0950-9232, 1476-5594, 1476-5594
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Popis
Shrnutí:We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. Aiming to exploit this effect in therapy we performed a compound screen in five breast cancer cell lines with IGF neutralising antibody xentuzumab. Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. Co-inhibition of IGF and CHK1 caused synergistic suppression of cell viability, cell survival and tumour growth in 2D cell culture, 3D spheroid cultures and in vivo. Investigating the mechanism of synthetic lethality, we reveal that CHK1 inhibition in IGF-1R depleted or inhibited cells further downregulated RRM2, reduced dNTP supply and profoundly delayed replication fork progression. These effects resulted in significant accumulation of unreplicated single-stranded DNA and increased cell death, indicative of replication catastrophe. Similar phenotypes were induced by IGF:WEE1 co-inhibition, also via exacerbation of RRM2 downregulation. Exogenous RRM2 expression rescued hallmarks of replication stress induced by co-inhibiting IGF with CHK1 or WEE1, identifying RRM2 as a critical target of the functional IGF:CHK1 and IGF:WEE1 interactions. These data identify novel therapeutic vulnerabilities and may inform future trials of IGF inhibitory drugs.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-021-02080-1