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

Oplustil O'Connor, Lenka; Rulten, Stuart L; Cranston, Aaron N; Odedra, Rajesh; Brown, Henry; Jaspers, Janneke E; Jones, Louise; Knights, Charlotte; Evers, Bastiaan; Ting, Attilla; Bradbury, Robert H; Pajic, Marina; Rottenberg, Sven; Jonkers, Jos; Rudge, David; Martin, Niall M B; Caldecott, Keith W; Lau, Alan; O'Connor, Mark J (2016). The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models. Cancer research, 76(20), pp. 6084-6094. American Association for Cancer Research AACR 10.1158/0008-5472.CAN-15-3240

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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. Cancer Res; 76(20); 6084-94. ©2016 AACR.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0008-5472

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

07 Jul 2017 13:55

Last Modified:

07 Jul 2017 13:55

Publisher DOI:

10.1158/0008-5472.CAN-15-3240

PubMed ID:

27550455

BORIS DOI:

10.7892/boris.96719

URI:

https://boris.unibe.ch/id/eprint/96719

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