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A chromatin modifier genetic screen identifies SIRT2 as a modulator of response to targeted therapies through the regulation of MEK kinase activity

Oncogene volume 34, pages 531–536 (2015)Cite this article

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Abstract

Resistance to targeted therapies is a major problem in cancer treatment. The epidermal growth factor receptor (EGFR) antibody drugs are effective in a subset of colorectal cancers, but the molecular mechanisms of resistance are understood poorly. Genes involved in epigenetic regulation are frequently deregulated in cancer, raising the possibility that such genes also contribute to drug resistance. Using a focused RNA interference library for genes involved in epigenetic regulation, we identify sirtuin2 (SIRT2), an NAD+-dependent deacetylase, as a modulator of the response to EGFR inhibitors in colon and lung cancer. SIRT2 loss also conferred resistance to BRAF and MEK inhibitors in BRAF mutant melanoma and KRAS mutant colon cancers, respectively. These results warrant further investigation into the potential role of SIRT2 in resistance to drugs that act in the receptor tyrosine kinase-RAS-RAF-MEK-ERK signaling pathway.

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Acknowledgements

We are grateful to Kees Punt, Sabine Tejpar, Josep Tabernero, Jose Jimenez, Adriana López-Dóriga Guerra, Ramon Salzar and Loredana Vecchione for providing clinical specimen of cetuximab-treated colon cancers. We thank Gerrit Hooiger and Marc van de Vijver (AMC, Amsterdam) for assistance in staining tissue microarrays and Alberto Bardelli for the kind gift of the Difi cells. We thank the NKI Genomics Core Facility, especially Iris de Rink, for support. We also thank Chong Sun and Sidong Huang for helpful discussions. This work was supported by grants from the Dutch Cancer Society (KWF) and the European Union Seventh Framework Program COLTHERES project, grant agreement 259015.

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Author notes

  1. P K Bajpe and A Prahallad: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Carcinogenesis, Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    P K Bajpe, A Prahallad, H Horlings, R Beijersbergen & R Bernards

  2. Department of Pathology, Academisch Medisch Centrum, Amsterdam, The Netherlands

    H Horlings

  3. Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    I Nagtegaal

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  1. P K Bajpe
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Correspondence to R Bernards.

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Bajpe, P., Prahallad, A., Horlings, H. et al. A chromatin modifier genetic screen identifies SIRT2 as a modulator of response to targeted therapies through the regulation of MEK kinase activity. Oncogene 34, 531–536 (2015). https://doi.org/10.1038/onc.2013.588

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