MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small cell lung cancer. MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small cell lung cancer

Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first line therapy readily, rapid relapse is inevitable with few treatment options in the second line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN, but not MYCL1 nor non-amplified MYC cell lines, exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor Mivebresib (ABBV-075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the anti-proliferative effects of mivebresib. Furthermore, the activity of mivebresib in SCLC cell lines occurs primarily through BRD2, rather than BRD4. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Our study suggests that chromatin landscapes could establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib. Overall design: Chromatin-Immunoprecipitation DNA sequencing (ChIP-seq) was performed using H3K27ac, MYC, MYCL, and MYCN antibodies in SCLC cell lines. ATAC-seq was also performed in SCLC cell lines.

小细胞肺癌（Small-cell lung cancer, SCLC）约占所有肺癌病例的15%。尽管患者可对一线治疗快速产生应答，但二线治疗场景下几乎无可用治疗方案，且疾病快速复发难以避免。本研究发现，携带MYC与MYCN扩增、而非MYCL1扩增或MYC未扩增的小细胞肺癌细胞系，对泛BET溴结构域蛋白抑制剂Mivebresib（ABBV-075）的治疗展现出优异敏感性。对MYC与MYCN进行基因沉默，可部分挽救携带对应扩增的小细胞肺癌细胞系，使其免受Mivebresib的抗增殖作用影响。此外，Mivebresib在小细胞肺癌细胞系中的作用主要通过BRD2介导，而非BRD4。对MYC、MYCN及MYCL1的全基因组结合特征进行进一步表征后，发现其具有独特的增强子结合偏好与表观遗传特征。本研究表明，染色质调控图谱可通过塑造独特的基因表达程序来确定细胞状态，从而使细胞对Mivebresib这类表观遗传抑制剂产生敏感性。整体实验设计：采用针对H3K27ac、MYC、MYCL及MYCN的抗体，在小细胞肺癌细胞系中开展染色质免疫沉淀测序（Chromatin-Immunoprecipitation DNA sequencing, ChIP-seq）实验；同时在小细胞肺癌细胞系中开展了ATAC-seq实验。