Corpus ID: 34488651

The PARP inhibitor AZD 2461 is differentiated from olaparib for both PARP 3 activity and drug resistance

  title={The PARP inhibitor AZD 2461 is differentiated from olaparib for both PARP 3 activity and drug resistance},
  author={Lenka Oplustil O’Connor and Stuart L. Rulten and Aaron N. Cranston and Rajesh Odedra and Henry Brown and Janneke E. Jaspers and Louise A. Jones and Charlotte Knights and Bastiaan Evers and Attilla Ting and Robert Hugh Bradbury and Marina Pajic and Sven Rottenberg and Jos Jonkers and David Alan Rudge and Niall M. B. Martin and Keith W. Caldecott and Alan Y K Lau and Mark J. O'Connor},


Rationale for PARP inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition
Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (J.M., Y.P.)Expand
Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors.
This study shows that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA, providing a new mechanistic foundation for the rational application ofPARP inhibitors in cancer therapy. Expand
The role of PARP in DNA repair and its therapeutic exploitation
Recent studies indicate that tumour cells with defective homologous recombination (HR) repair pathways are exquisitely sensitive to PARPi, and the identification of predictive markers for sensitivity to PARP inhibition is a priority area for research. Expand
High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs
In vivo efficacy of AZD2281 against BRCA1-deficient breast cancer is demonstrated and how GEMMs of cancer can be used for preclinical evaluation of novel therapeutics and for testing ways to overcome or circumvent therapy resistance is illustrated. Expand
Novel alkoxybenzamide inhibitors of poly(ADP-ribose) polymerase.
A novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors. Expand
PARP-3 and APLF function together to accelerate nonhomologous end-joining.
Molecular roles for PARP-3 and APLF in chromosomal DNA double-strand break repair reactions are identified and it is shown that class switch recombination in Aplf(-/-) B cells is biased toward microhomology-mediated end-joining. Expand
Homologous recombination-deficient tumors are hyper-dependent on POLQ-mediated repair
The results reveal a synthetic lethal relationship between the HR pathway and Polθ-mediated repair in EOCs, and identifyPolθ as a novel druggable target for cancer therapy. Expand
Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination
Next-generation sequencing technology is used to show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes. Expand
REV7 counteracts DNA double-strand break resection and affects PARP inhibition
This work shows that loss of REV7 in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. Expand
and Drug Administration (FDA)
  • FDA News Release: FDA approves Lynparza to treat advanced ovarian cancer, 2014. Available at, accessed on 23 June
  • 2015