NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model.

Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line-derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709-17. ©2018 AACR.

[1]  Guocheng Yuan,et al.  Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer. , 2017, Cancer discovery.

[2]  D. MacPherson,et al.  Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance) , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[3]  C. Rudin,et al.  Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis. , 2017, Cancer cell.

[4]  A. Gazdar,et al.  Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer , 2016, Genes & development.

[5]  R. Myers,et al.  Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes , 2016, Cancer Immunology Research.

[6]  J. H. Richardson,et al.  The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models , 2016, Oncogene.

[7]  P. Ross-Macdonald,et al.  Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression , 2015, Molecular Cancer Therapeutics.

[8]  Yan Liu,et al.  Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. , 2014, Cancer cell.

[9]  B. Zabel,et al.  Anti-Asialo GM1 NK Cell Depleting Antibody Does Not Alter the Development of Bleomycin Induced Pulmonary Fibrosis , 2014, PloS one.

[10]  E. Seto,et al.  Erasers of histone acetylation: the histone deacetylase enzymes. , 2014, Cold Spring Harbor perspectives in biology.

[11]  Travis J Cohoon,et al.  Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. , 2013, Cancer discovery.

[12]  R. Heist,et al.  Multidisciplinary management of small cell lung cancer. , 2013, Surgical oncology clinics of North America.

[13]  Travis J Cohoon,et al.  Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. , 2013, Cancer cell.

[14]  H. Varmus,et al.  Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins , 2012, Proceedings of the National Academy of Sciences.

[15]  H. Borghaei,et al.  Personalized medicine and treatment approaches in non-small-cell lung carcinoma , 2012, Pharmacogenomics and personalized medicine.

[16]  W. Cho,et al.  肺癌的个体化靶向治疗 , 2013, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[17]  K. Cibulskis,et al.  Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer , 2012, Nature Genetics.

[18]  Robert Gentleman,et al.  Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer , 2012, Nature Genetics.

[19]  E. Seto,et al.  Modulation of Histone Deacetylase 6 (HDAC6) Nuclear Import and Tubulin Deacetylase Activity through Acetylation* , 2012, The Journal of Biological Chemistry.

[20]  A. Rossi,et al.  Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  J. Bradner,et al.  Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. , 2012, Blood.

[22]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[23]  H. Karasuyama,et al.  NK Cell-Depleting Anti-Asialo GM1 Antibody Exhibits a Lethal Off-Target Effect on Basophils In Vivo , 2011, The Journal of Immunology.

[24]  William B. Smith,et al.  Selective inhibition of BET bromodomains , 2010, Nature.

[25]  R. Lilenbaum,et al.  Small Cell Lung Cancer: Past, Present, and Future , 2010, Current oncology reports.

[26]  John H. White,et al.  Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR* , 2009, The Journal of Biological Chemistry.

[27]  Dustin E. Schones,et al.  Genome-wide Mapping of HATs and HDACs Reveals Distinct Functions in Active and Inactive Genes , 2009, Cell.

[28]  Michael J. Emanuele,et al.  A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene , 2009, Cell.

[29]  N. Hacohen,et al.  Highly parallel identification of essential genes in cancer cells , 2008, Proceedings of the National Academy of Sciences.

[30]  F. Sánchez‐Madrid,et al.  HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. , 2008, Trends in cell biology.

[31]  Michael Peyton,et al.  Synthetic lethal screen identification of chemosensitizer loci in cancer cells , 2007, Nature.

[32]  D. Jackman,et al.  Small-cell lung cancer , 2005, The Lancet.

[33]  Qiang Zhou,et al.  Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. , 2005, Molecular cell.

[34]  A. V. van Kuilenburg,et al.  Histone deacetylases (HDACs): characterization of the classical HDAC family. , 2003, The Biochemical journal.

[35]  S. K. Zaidi,et al.  Runx2 (Cbfa1, AML-3) Interacts with Histone Deacetylase 6 and Represses the p21CIP1/WAF1 Promoter , 2002, Molecular and Cellular Biology.

[36]  B. Johnson,et al.  Management of small-cell lung cancer. , 2002, Clinics in chest medicine.

[37]  S. Schreiber,et al.  Three proteins define a class of human histone deacetylases related to yeast Hda1p. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Duvic New member of the winged-helix protein family disrupted in mouse and rat nude mutations , 1995 .

[39]  E. Klein,et al.  MHC antigens on human tumors. , 1991, Immunology letters.

[40]  G. Kalemkerian,et al.  Small cell lung cancer , 2010, Seminars in Respiratory and Critical Care Medicine.

[41]  S. Flanagan,et al.  'Nude', a new hairless gene with pleiotropic effects in the mouse. , 1966, Genetical research.

[42]  L. Terracciano,et al.  HLA class II antigen expression in colorectal carcinoma tumors as a favorable prognostic marker. , 2014, Neoplasia.

[43]  S. Gadgeel,et al.  Modern staging of small cell lung cancer. , 2013, Journal of the National Comprehensive Cancer Network : JNCCN.

[44]  P. Atadja,et al.  The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance , 2009, Nature Immunology.