Characterizing functional DNA damage and response caused by the combination of CHK1 and WEE1 inhibitors in ovarian and breast cancer models.
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Embargo End Date
ICR Authors
Authors
Stewart, A
Song, J
Pickard, L
Muggiolu, G
Sauvaigo, S
Brandon, ADH
Raynaud, F
Banerji, U
Song, J
Pickard, L
Muggiolu, G
Sauvaigo, S
Brandon, ADH
Raynaud, F
Banerji, U
Document Type
Journal Article
Date
2024-04-03
Date Accepted
2024-01-31
Abstract
BACKGROUND: We proposed to quantify reduction of functional DNA damage response (DDR) mechanisms caused by the combination of CHK1 and WEE1 inhibitors. METHODS: Survival of cells and tumor growth in-vitro and in-vivo caused by the combination of the CHK1 inhibitor SRA737 and the WEE1 inhibitor adavosertib was studied in OVCAR3 and MDA-MB 436 cells. Functional DNA damage was quantified using in vitro cell free DNA assays. RESULTS: The combination of SRA737 and adavosertib caused significant reduction of survival of cells and DNA damage in-vitro and growth inhibition in-vivo. Studies using functional DDR assays found significant changes in the functional capacity of OVCAR3 but not MDA-MB 436 cells to repair DNA damage using multiple mechanisms including intra strand cross link repair, nucleotide excision repair, homologous recombination and non-homologous end joining. This study, for the first time provides a mechanistic insight into differences in the reduction in functional capacity of cells to repair DNA when exposed to CHK1 and WEE1 inhibitors. CONCLUSION: The combination of the CHK1 inhibitor SRA737 and WEE1 inhibitor adavosertib causes growth inhibition in-vitro and in-vivo, but differential functional inhibition of DDR in the models studied.
Citation
BJC Reports, 2024, 2 (1),
Source Title
BJC Reports
Publisher
SPRINGERNATURE
ISSN
eISSN
2731-9377
2731-9377
2731-9377
Collections
Research Team
Clinical Pharmacology