The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models

被引：48

作者：

O'Connor, Lenka Oplustil ^{[1
,6
]}

Rulten, Stuart L. ^{[2
]}

Cranston, Aaron N. ^{[3
]}

Odedra, Rajesh ^{[1
]}

Brown, Henry ^{[1
]}

Jaspers, Janneke E. ^{[4
,5
]}

Jones, Louise ^{[3
]}

Knights, Charlotte ^{[3
]}

Evers, Bastiaan ^{[5
]}

Ting, Attilla ^{[1
]}

Bradbury, Robert H. ^{[1
]}

Pajic, Marina ^{[4
,8
]}

Rottenberg, Sven ^{[4
,7
]}

Jonkers, Jos ^{[5
]}

Rudge, David ^{[1
]}

Martin, Niall M. B. ^{[3
]}

Caldecott, Keith W. ^{[2
]}

Lau, Alan ^{[1
]}

O'Connor, Mark J. ^{[1
,6
]}

机构：

[1] AstraZeneca, Alderley Pk, Macclesfield, Cheshire, England

[2] Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England

[3] KuDOS Pharmaceut Ltd, Cambridge, England

[4] Netherlands Canc Inst, Div Mol Oncol, Amsterdam, Netherlands

[5] Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands

[6] AstraZeneca, Cambridge, England

[7] Univ Bern, Inst Anim Pathol, Vetsuisse Fac, Bern, Switzerland

[8] Kinghorn Canc Ctr, Garvan Inst Med Res, Personalised Canc Therapeut, Darlinghurst, NSW, Australia

来源：

CANCER RESEARCH | 2016年 / 76卷 / 20期

关键词：

STRAND BREAK REPAIR; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS-RECOMBINATION; MAMMARY-TUMORS; DNA-DAMAGE; CANCER-THERAPY; CELLS; BRCA1; COMBINATION; RESISTANCE;

D O I：

10.1158/0008-5472.CAN-15-3240

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. (C) 2016 AACR.

引用

页码：6084 / 6094

页数：11