acy-1215 and Lung-Neoplasms

Topics: Acetylation; Animals; Apoptosis; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Synergism; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lung Neoplasms; Mice; Mice, Inbred C57BL; Paclitaxel; Quinazolinones; Structure-Activity Relationship; Tissue Distribution; Transplantation, Homologous; Tubulin

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Azepines; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Histone Deacetylase 6; Humans; Hydroxamic Acids; Killer Cells, Natural; Lung Neoplasms; Mice; Neoplasm Recurrence, Local; Proteins; Pyrimidines; RNA, Small Interfering; Small Cell Lung Carcinoma; Synthetic Lethal Mutations; Treatment Outcome; Triazoles; Xenograft Model Antitumor Assays