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

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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6450092 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Liu Yan Y Li Yuyang Y Liu Shengwu S Adeegbe Dennis O DO Christensen Camilla L CL Quinn Max M MM Dries Ruben R Han Shiwei S Buczkowski Kevin K Wang Xiaoen X Chen Ting T Chen Ting T Gao Peng P Zhang Hua H Li Fei F Hammerman Peter S PS Bradner James E JE Quayle Steven N SN Wong Kwok-Kin KK

Cancer research 20180514 13

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 scre ...[more]

PMID: 29760044

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Dataset Information

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

Publications

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

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