Reference Detail

Ref Type Journal Article
PMID (27550455)
Authors Oplustil O'Connor L, Rulten SL, Cranston AN, Odedra R, Brown H, Jaspers JE, Jones L, Knights C, Evers B, Ting A, Bradbury RH, Pajic M, Rottenberg S, Jonkers J, Rudge D, Martin NM, Caldecott KW, Lau A, O'Connor MJ
Title The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models.
Journal Cancer research
Vol 76
Issue 20
Date 2016 Oct 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
AZD2461 AZD2461 inhibits PARP1 and PARP2, resulting in decreased tumor cell growth (PMID: 27550455).
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD2461 PARP Inhibitor (Pan) 17 AZD2461 inhibits PARP1 and PARP2, resulting in decreased tumor cell growth (PMID: 27550455).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRCA2 inact mut breast cancer sensitive AZD2461 Preclinical - Cell culture Actionable In a preclinical study, a BRCA2-deficient breast cancer cell line resistant to Lynparza (olaparib) demonstrated sensitivity to treatment with AZD2461 in culture, resulting in reduced cell viability (PMID: 27550455). 27550455
BRCA1 loss TP53 loss breast cancer sensitive AZD2461 Preclinical Actionable In a preclinical study, a breast cancer model lacking both BRCA1 and TP53 demonstrated sensitivity to treatment with AZD2461, which resulted in decreased tumor volume (PMID: 27550455). 27550455
Unknown unknown colorectal cancer not applicable Olaparib + Temozolomide Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of Lynparza (olaparib) to Temodar (temozolomide) resulted in greater antitumor activity than Temodar (temozolomide) alone in colorectal cancer cell line xenograft models, demonstrating decreased tumor volume (PMID: 27550455). 27550455
Unknown unknown colorectal cancer not applicable AZD2461 + Temozolomide Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of AZD2461 to Temodar (temozolomide) resulted in greater antitumor activity than Temodar (temozolomide) alone in colorectal cancer cell line xenograft models, demonstrating decreased tumor volume (PMID: 27550455). 27550455
BRCA1 mutant breast cancer sensitive AZD2461 Preclinical - Cell culture Actionable In a preclinical study, AZD2461 inhibited the growth of BRCA1 mutant breast cancer cells in culture (PMID: 27550455). 27550455