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MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation

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Summary

The poly-(ADP-ribose) polymerase (PARP) inhibitor, MK-4827, is a novel potent, orally bioavailable PARP-1 and PARP-2 inhibitor currently in phase I clinical trials for cancer treatment. No preclinical data currently exist on the combination of MK-4827 with radiotherapy. The current study examined combined treatment efficacy of MK-4827 and fractionated radiotherapy using a variety of human tumor xenografts of differing p53 status: Calu-6 (p53 null), A549 (p53 wild-type [wt]) and H-460 (p53 wt) lung cancers and triple negative MDA-MB-231 human breast carcinoma. To mimic clinical application of radiotherapy, fractionated radiation (2 Gy per fraction) schedules given once or twice daily for 1 to 2 weeks combined with MK-4827, 50 mg/kg once daily or 25 mg/kg twice daily, were used. MK-4827 was found to be highly and similarly effective in both radiation schedules but maximum radiation enhancement was observed when MK-4827 was given at a dose of 50 mg/kg once daily (EF = 2.2). MK-4827 radiosensitized all four tumors studied regardless of their p53 status. MK-4827 reduced PAR levels in tumors by 1 h after administration which persisted for up to 24 h. This long period of PARP inhibition potentially adds to the flexibility of design of future clinical trials. Thus, MK-4827 shows high potential to improve the efficacy of radiotherapy.

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Acknowledgement

This study was sponsored by a Laboratory Study Agreement with Merck Sharp & Dohme Corp.

Conflict of Interest

Authors Anjili Mathur, Carolyn Buser-Doepner and Carlo Toniatti are current or former employees of Merck Sharp & Dohme Corp.

All other authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Li Wang, Kathy A. Mason, David Valdecanas & Luka Milas

  2. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    K. Kian Ang & Thomas Buchholz

  3. Department of Oncology, Merck Research Labs, 33 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Anjili Mathur, Carolyn Buser-Doepner & Carlo Toniatti

Authors
  1. Li Wang
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  2. Kathy A. Mason
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  3. K. Kian Ang
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  4. Thomas Buchholz
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  5. David Valdecanas
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  6. Anjili Mathur
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  7. Carolyn Buser-Doepner
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  8. Carlo Toniatti
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  9. Luka Milas
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Correspondence to Li Wang.

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Wang, L., Mason, K.A., Ang, K.K. et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs 30, 2113–2120 (2012). https://doi.org/10.1007/s10637-011-9770-x

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  • DOI: https://doi.org/10.1007/s10637-011-9770-x

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