NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model
Year: 2018
Type: article
Abstract: 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.
Source: Cancer Research
Language: English
Topic: Lung Cancer Research Studies
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Mechanisms of tumorigenesis in Brg1 mutant lung cancer, MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer, G2018972360, In vivo analysis of EGFR mutant driven lung cancers responses to radiation therap, Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer, Credentialing Mouse Models for Immune System Therapy Research, MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies, Therapeutic strategies for specific subsets of KRAS mutant lung cancers, G3891858173, Investigation and targeting of the transcriptional and epigenetic landscape of Small Cell Lung Cancer, G6756496003, G77253623, Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors., In vivo murine models of metastasis for therapeutic testing, G982405977
OpenAlex ID: W2803891124