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Published on: February 6, 2015
Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin
Bastiaan Evers1, Rinske Drost, Eva Schut
1Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Purpose:
To assess efficacy of the novel, selective poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between AZD2281 and cisplatin.
Experimental Design:
We established and thoroughly characterized a panel of clonal cell lines from independent BRCA2-deficient mouse mammary tumors and BRCA2-proficient control tumors. Subsequently, we assessed sensitivity of these lines to conventional cytotoxic drugs and the novel PARP inhibitor AZD2281. Finally, in vitro combination studies were done to investigate interaction between AZD2281 and cisplatin.
Results:
Genetic, transcriptional, and functional analyses confirmed the successful isolation of BRCA2-deficient and BRCA2-proficient mouse mammary tumor cell lines. Treatment of these cell lines with 11 different anticancer drugs or with gamma-irradiation showed that AZD2281, a novel and specific PARP inhibitor, caused the strongest differential growth inhibition of BRCA2-deficient versus BRCA2-proficient mammary tumor cells. Finally, drug combination studies showed synergistic cytotoxicity of AZD2281 and cisplatin against BRCA2-deficient cells but not against BRCA2-proficient control cells.
Conclusion:
We have successfully established the first set of BRCA2-deficient mammary tumor cell lines, which form an important addition to the existing preclinical models for BRCA-mutated breast cancer. The exquisite sensitivity of these cells to the PARP inhibitor AZD2281, alone or in combination with cisplatin, provides strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.
Insights
The poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 effectively targets BRCA2-deficient mammary tumors. Combining AZD2281 with cisplatin shows synergistic effects in BRCA2-deficient cells, supporting its use in treating BRCA-mutated cancers.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- BRCA2 mutations are linked to increased breast cancer risk.
- Targeted therapies are crucial for treating BRCA-mutated cancers.
- PARP inhibitors represent a promising class of targeted cancer drugs.
Purpose of the Study:
- To evaluate the efficacy of the PARP-1 inhibitor AZD2281 in novel BRCA2-deficient mouse mammary tumor cell lines.
- To investigate potential synergistic effects between AZD2281 and cisplatin in these models.
Main Methods:
- Established and characterized BRCA2-deficient and BRCA2-proficient mouse mammary tumor cell lines.
- Assessed sensitivity to various anticancer drugs and AZD2281.
- Conducted in vitro combination studies with AZD2281 and cisplatin.
Main Results:
- AZD2281 demonstrated significant differential growth inhibition of BRCA2-deficient cells compared to BRCA2-proficient cells.
- Combination therapy with AZD2281 and cisplatin exhibited synergistic cytotoxicity against BRCA2-deficient cells.
- No synergistic effect was observed in BRCA2-proficient control cells.
Conclusions:
- Successfully developed preclinical models for BRCA-deficient mammary tumors.
- AZD2281 shows potent activity against BRCA2-deficient cells, alone and in combination with cisplatin.
- These findings support AZD2281 as a targeted therapeutic for BRCA-deficient cancers.
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