A chromatin modifier genetic screen identifies SIRT2 as a modulator of response to targeted therapies through the regulation of MEK kinase activity.
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.
Division of Molecular Carcinogenesis, Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Bajpe
Division of Molecular Carcinogenesis, Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Prahallad
1] Division of Molecular Carcinogenesis, Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands [2] Department of Pathology, Academisch Medisch Centrum, Amsterdam, The Netherlands.
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Horlings
Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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Nagtegaal
Division of Molecular Carcinogenesis, Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Beijersbergen
Division of Molecular Carcinogenesis, Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Bernards
D000107:Acetylation; D049109:Cell Proliferation; D002843:Chromatin; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D056565:Sirtuin 2 / Q000502:physiology*
D002843:Chromatin; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C474199:SIRT2 protein, human; D056565:Sirtuin 2