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A high-throughput screen identifies PARP1/2 inhibitors as a potential therapy for ERCC1-deficient non-small cell lung cancer

Oncogene volume 32, pages 5377–5387 (2013)Cite this article

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Abstract

Excision repair cross-complementation group 1 (ERCC1) is a DNA repair enzyme that is frequently defective in non-small cell lung cancer (NSCLC). Although low ERCC1 expression correlates with platinum sensitivity, the clinical effectiveness of platinum therapy is limited, highlighting the need for alternative treatment strategies. To discover new mechanism-based therapeutic strategies for ERCC1-defective tumours, we performed high-throughput drug screens in an isogenic NSCLC model of ERCC1 deficiency and dissected the mechanism underlying ERCC1-selective effects by studying molecular biomarkers of tumour cell response. The high-throughput screens identified multiple clinical poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors, such as olaparib (AZD-2281), niraparib (MK-4827) and BMN 673, as being selective for ERCC1 deficiency. We observed that ERCC1-deficient cells displayed a significant delay in double-strand break repair associated with a profound and prolonged G2/M arrest following PARP1/2 inhibitor treatment. Importantly, we found that ERCC1 isoform 202, which has recently been shown to mediate platinum sensitivity, also modulated PARP1/2 sensitivity. A PARP1/2 inhibitor-synthetic lethal siRNA screen revealed that ERCC1 deficiency was epistatic with homologous recombination deficiency. However, ERCC1-deficient cells did not display a defect in RAD51 foci formation, suggesting that ERCC1 might be required to process PARP1/2 inhibitor-induced DNA lesions before DNA strand invasion. PARP1 silencing restored PARP1/2 inhibitor resistance in ERCC1-deficient cells but had no effect in ERCC1-proficient cells, supporting the hypothesis that PARP1 might be required for the ERCC1 selectivity of PARP1/2 inhibitors. This study suggests that PARP1/2 inhibitors as a monotherapy could represent a novel therapeutic strategy for NSCLC patients with ERCC1-deficient tumours.

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Acknowledgements

We thank David Roberston and Marieke Aarts for assistance with confocal microscopy and FACS analysis, and Jerry Shen and Len Post at Biomarin for the provision of BMN 673. We also acknowledge NHS funding to the NIHR Royal Marsden Hospital BRC. This work was supported by grants from Cancer Research UK and The European Union as part of the FP7 teams ‘DDResponse’ and ‘Eurocan’. SPV is supported by a Translational Research Fellowship from the European Society of Medical Oncology (2011 and 2012) and by funding from the Institut National du Cancer: Bourse pour la Formation à la Recherche Translationnelle (2011)

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Authors and Affiliations

  1. The Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Institute of Cancer Research, London, UK

    S Postel-Vinay, I Bajrami, R Elliott, Y Fontebasso, C J Lord & A Ashworth

  2. Département de médecine—Unité INSERM 981, Institut Gustave Roussy, Villejuif, France

    S Postel-Vinay, L Friboulet, N Dorvault, K A Olaussen, F André & J-C Soria

  3. Université Paris-Sud XI, Paris, France

    K A Olaussen, F André & J-C Soria

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Correspondence to C J Lord or A Ashworth.

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Competing interests

AA and CJL are inventors on patents describing the use of PARP inhibitors and may benefit from the ICR ‘Rewards to inventors scheme’. All other authors declare no conflicts of interest.

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Postel-Vinay, S., Bajrami, I., Friboulet, L. et al. A high-throughput screen identifies PARP1/2 inhibitors as a potential therapy for ERCC1-deficient non-small cell lung cancer. Oncogene 32, 5377–5387 (2013). https://doi.org/10.1038/onc.2013.311

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