Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Bastiaan
B
Evers
Rinske
R
Drost
Eva
E
Schut
Michiel
M
de Bruin
Eline
E
van der Burg
Patrick W B
PW
Derksen
Henne
H
Holstege
Xiaoling
X
Liu
Ellen
E
van Drunen
H Berna
HB
Beverloo
Graeme C M
GC
Smith
Niall M B
NM
Martin
Alan
A
Lau
Mark J
MJ
O'Connor
Jos
J
Jonkers
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage*; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000528:radiation effects; D010793:Phthalazines / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase / Q000235:genetics
D000970:Antineoplastic Agents; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase; D002945:Cisplatin; C531550:olaparib