Poly (ADP-Ribose) polymerase inhibitor hypersensitivity in aggressive myeloproliferative neoplasms

Keith W. Pratz, Brian D. Koh, Anand G. Patel, Karen S. Flatten, Weijie Poh, James G. Herman, Robert Dilley, Maria I. Harrell, B. Douglas Smith, Judith E. Karp, Elizabeth M. Swisher, Michael A. McDevitt, Scott H. Kaufmann

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo. Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes. Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894-902. Ó2016 AACR.

Original languageEnglish (US)
Pages (from-to)3894-3902
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number15
DOIs
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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