Modeling Therapy Resistance in BRCA1/2-Mutant Cancers.
Date
2017-09-01ICR Author
Author
Dréan, A
Williamson, CT
Brough, R
Brandsma, I
Menon, M
Konde, A
Garcia-Murillas, I
Pemberton, HN
Frankum, J
Rafiq, R
Badham, N
Campbell, J
Gulati, A
Turner, NC
Pettitt, SJ
Ashworth, A
Lord, CJ
Type
Journal Article
Metadata
Show full item recordAbstract
Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 Whether secondary mutant tumor cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR mutagenesis, we generated isogenic tumor cell models with secondary BRCA1 or BRCA2 mutations. Using these in heterogeneous in vitro culture or in vivo xenograft experiments in which the clonal composition of tumor cell populations in response to therapy was monitored, we established that PARP inhibitor or platinum salt exposure selects for secondary mutant clones in a Darwinian fashion, with the periodicity of PARP inhibitor administration and the pretreatment frequency of secondary mutant tumor cells influencing the eventual clonal composition of the tumor cell population. In xenograft studies, the presence of secondary mutant cells in tumors impaired the therapeutic effect of a clinical PARP inhibitor. However, we found that both PARP inhibitor-sensitive and PARP inhibitor-resistant BRCA2 mutant tumor cells were sensitive to AZD-1775, a WEE1 kinase inhibitor. In mice carrying heterogeneous tumors, AZD-1775 delivered a greater therapeutic benefit than olaparib treatment. This suggests that despite the restoration of some BRCA1 or BRCA2 gene function in "revertant" tumor cells, vulnerabilities still exist that could be therapeutically exploited. Mol Cancer Ther; 16(9); 2022-34. ©2017 AACR.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Disease Models, Animal
Pyrazoles
Pyrimidines
Pyrimidinones
Cell Cycle Proteins
BRCA1 Protein
BRCA2 Protein
Nuclear Proteins
Antineoplastic Agents
Xenograft Model Antitumor Assays
DNA Mutational Analysis
Cell Cycle
Drug Resistance, Neoplasm
Mutation
Female
Protein-Tyrosine Kinases
Gene Knockdown Techniques
Selection, Genetic
Poly(ADP-ribose) Polymerase Inhibitors
Research team
Molecular Oncology
Gene Function
Language
eng
Date accepted
2017-06-05
License start date
2017-09
Citation
Molecular cancer therapeutics, 2017, 16 (9), pp. 2022 - 2034
Publisher
AMER ASSOC CANCER RESEARCH
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