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.