MYC Family Amplification Dictates Sensitivity to BET Bromodomain Protein Inhibitor Mivebresib (ABBV075) in Small-Cell Lung Cancer.
Joshua P PlotnikZheng ZhaWeiguo FengIrene I LeeJacob RiehmRyan A McClureStephanie SandovalTamar UzielErin MurphyXin LuLloyd T LamPublished in: Molecular cancer research : MCR (2024)
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 or non-amplified MYC cell lines exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor mivebresib (ABBV075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the antiproliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes can establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.
Keyphrases
- gene expression
- transcription factor
- small cell lung cancer
- dna methylation
- genome wide
- binding protein
- end stage renal disease
- dna binding
- ejection fraction
- chronic kidney disease
- brain metastases
- nucleic acid
- protein protein
- dna damage
- prognostic factors
- peritoneal dialysis
- amino acid
- bone marrow
- oxidative stress
- small molecule