PARP inhibitors synergize with gemcitabine by potentiating DNA damage in non-small-cell lung cancer
Yu Jiang
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Department of Respiratory Medicine, The University-Town Hospital of Chongqing Medical University, Chongqing, China
Search for more papers by this authorHui Dai
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Search for more papers by this authorYang Li
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Search for more papers by this authorJun Yin
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Search for more papers by this authorShuliang Guo
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
Search for more papers by this authorCorresponding Author
Shiaw-Yih Lin
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Correspondence to: Shiaw-Yih Lin, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]; or Daniel J. McGrail, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Daniel J. McGrail
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Correspondence to: Shiaw-Yih Lin, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]; or Daniel J. McGrail, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]Search for more papers by this authorYu Jiang
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Department of Respiratory Medicine, The University-Town Hospital of Chongqing Medical University, Chongqing, China
Search for more papers by this authorHui Dai
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Search for more papers by this authorYang Li
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Search for more papers by this authorJun Yin
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Search for more papers by this authorShuliang Guo
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
Search for more papers by this authorCorresponding Author
Shiaw-Yih Lin
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Correspondence to: Shiaw-Yih Lin, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]; or Daniel J. McGrail, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Daniel J. McGrail
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Correspondence to: Shiaw-Yih Lin, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]; or Daniel J. McGrail, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Tel.: +1-713-563-4217, E-mail: [email protected]Search for more papers by this authorAbstract
Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise in the treatment of patients with deficiencies in homologous recombination (HR) DNA repair, such as those with loss of BRCA1 or BRCA2 function. However, emerging studies suggest that PARP inhibition can also target HR-competent cancers, such as non-small-cell lung cancer (NSCLC), and that the therapeutic effect of PARP inhibition may be improved by combination with chemotherapy agents. In our study, it was found that PARP inhibitors talazoparib (BMN-673) and olaparib (AZD-2281) both had synergistic activity with the common first-line chemotherapeutic gemcitabine in a panel of lung cancer cell lines. Furthermore, the combination demonstrated significant in vivo antitumor activity in an H23 xenograft model of NSCLC compared to either agent as monotherapy. This synergism occurred without loss of HR repair efficiency. Instead, the combination induced synergistic single-strand DNA breaks, leading to accumulation of toxic double-strand DNA lesions in vitro and in vivo. Our study elucidates the underlying mechanisms of synergistic activity of PARP inhibitors and gemcitabine, providing a strong motivation to pursue this combination as an improved therapeutic regimen.
Abstract
What's new?
Inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) are promising agents for the treatment of non-small cell lung cancer (NSCLC). Whether their effectiveness is augmented by combination with other therapies, however, remains unclear. In this study, PARP inhibitors were found to act synergistically against NSCLC cells and xenografts when combined with gemcitabine. Synergistic DNA damage induced by the combination treatment was dependent on the stalling of replication forks by gemcitabine. The failure of replication forks to recover in the presence of PARP inhibition likely leads to an increase in double-strand DNA breaks, resulting in greater cancer cell death.
Supporting Information
| Filename | Description |
|---|---|
| ijc31770-sup-0001-FigureS1.pdfPDF document, 105.8 KB | Supporting Information, Figure 1 Combination of gemcitabine of cisplatin. (a–c) Cell proliferation assay of H23, H522 and SK-MES-1 non-small-cell lung cancer cell lines were treated with varying concentrations of single agents or combinations of gemcitabine with cisplatin for 120 hr. Each value is relative to the value of cells treated with DMSO (control). Results are shown as mean ± SD from three independent experiments. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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