Talazoparib is a potent radiosensitizer in small cell lung cancer cell lines and xenografts Journal Article

Authors: Laird, J. H.; Lok, B. H.; Ma, J.; Bell, A.; de Stanchina, E.; Poirier, J. T.; Rudin, C. M.
Article Title: Talazoparib is a potent radiosensitizer in small cell lung cancer cell lines and xenografts
Abstract: Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization. Experimental Design: Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in 6 SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models. Results: Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays and confirmed in 3 of 3 cell lines by CSAs. Concentrations of 200 nmol/L talazoparib and 1,600 nmol/L veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization. This observation further correlated with an increased number of double-stranded DNA breaks induced by talazoparib as compared with veliparib. Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models. Conclusions: PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC. © 2018 AACR.
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 20
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-10-15
Start Page: 5143
End Page: 5152
Language: English
DOI: 10.1158/1078-0432.ccr-18-0401
PUBMED: 29945991
PROVIDER: scopus
Notes: Article -- Export Date: 1 November 2018 -- Source: Scopus
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MSK Authors
  1. Benjamin H Lok
    53 Lok
  2. Jennifer Ma
    34 Ma
  3. Charles Rudin
    161 Rudin
  4. John Thomas Poirier
    55 Poirier
  5. James   Laird
    13 Laird
  6. Andrew Carmen Bell
    11 Bell