Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin

Abstract

Purpose: To assess efficacy of the novel, selective poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between AZD2281and 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 AZD2281and 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 g-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 AZD2281as a novel targeted therapeutic against BRCA-deficient cancers.

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…This radiosensitization may result from PARP-mediated Targeting DDR pathways to improve cancer treatment F Al-Ejeh et al inhibition of single-strand break repair at stalled replication forks leading to the creation of DSBs (Haince et al, 2005). Consequently, up to 1000-fold higher sensitivity of BRCA-deficient (Bryant et al, 2005;Farmer et al, 2005;McCabe et al, 2005McCabe et al, , 2006Evers et al, 2008) or FA protein-deficient cells to PARP inhibition seems to depend on the excess of DSBs generated in the presence of compromised HR. Increased G2/M arrest upon PARP inhibition could explain the higher growth inhibition in FA proteindeficient cells .…”

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies

“…1 PARP inhibitors also impair, via other mechanisms, high fidelity repair of double-strand DNA breaks in tumor cells with deficiencies in homologous recombination repair (HRR), such as BRCA1/2 mutations (BRCA1/2m). 2,3 Impaired DNA repair in tumor cells with HRR deficiencies leads to irreparable double-strand breaks being formed that result in tumor cell death by synthetic lethality. 4 PARP inhibitors can also induce lethality in tumor cells that have deficiencies in DNA damage repair mechanisms other than HRR deficiencies.…”

Poly(ADP-ribose) polymerase inhibitors in triple-negative breast cancer

“…Preclinical studies then demonstrated that treatment with a PARP inhibitor had a significant impact on orthotopic transplants of BRCAnull breast cancers transplanted from conditional mutant mice. [21][22][23] Taken together, these studies have provided the preclinical rationale for exploring PARP inhibition as a strategy to treat malignancies in which the cells are deficient in HR-directed repair. The concept of using PARP inhibitors as single agents to induce cell death through synthetic lethality represents a novel approach to cancer treatment but may not be the only mechanism by which PARP inhibitors could improve cancer therapy.…”

“…36 Preclinical studies of combination therapy with PARP inhibitors and platinum agents animal models of BRCAdeficient breast cancers have shown enhanced efficacy (and toxicity). 21,37 The lack of HRdirected repair capability leads to cell death after exposure to the aggregate insult of doublestrand breaks resulting from the inability to repair platinum-induced crosslinks and similar breaks resulting from replication fork collapse at the site of SSB that are not repaired due to PARP inhibition.If there is a defect in HR-directed repair in subsets of TNBC, one would expect exquisite platinum sensitivity in that setting as well. Clinical studies examining this hypothesis are not conclusive, perhaps in part due to the heterogeneity of TNBC and the design of the available studies.…”