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.

中文翻译：

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在SCLC临床前模型中，NK细胞介导HDAC6和BET联合抑制的协同抗肿瘤作用。

在所有肺癌中，小细胞肺癌（SCLC）的恶性程度最高，表现出侵袭性生长和向远处的早期转移。30年来，SCLC的治疗选择仅限于化学疗法，因此需要更有效的治疗。TP53和RB1的频繁失活以及SCLC中的组蛋白失调提示转录和表观遗传调控在SCLC疾病演变中起主要作用。在这里，我们在治疗难治性SCLC异种移植模型中使用BET抑制剂JQ1和靶向550个表观遗传基因的shRNA文库进行了合成致死筛选，并将HDAC6与JQ1组合鉴定为合成致死靶标。HDAC6抑制剂ricolinostat（ACY-1215）和JQ1联合治疗人和小鼠SCLC细胞系来源的异种移植瘤表现出对肿瘤生长的显着抑制作用。NK细胞枯竭后，这种作用被取消，表明这些先天免疫淋巴样细胞在SCLC肿瘤治疗反应中起作用。总的来说，这些发现提示了一种潜在的复发性SCLC的新治疗方法。意义：这些发现确定了结合使用HDAC6和BET抑制剂的SCLC的新治疗策略。癌症研究；78（13）; 3709-17。©2018 AACR。意义：这些发现确定了结合使用HDAC6和BET抑制剂的SCLC新型治疗策略。癌症研究；78（13）; 3709-17。©2018 AACR。意义：这些发现确定了结合使用HDAC6和BET抑制剂的SCLC新型治疗策略。癌症研究；78（13）; 3709-17。©2018 AACR。