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Updated: Jun 26, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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MYC Family Amplification Dictates Sensitivity to BET Bromodomain Protein Inhibitor Mivebresib (ABBV075) in Small-Cell

Joshua P Plotnik1, Zheng Zha2, Weiguo Feng2

  • 1Oncology Discovery Research, AbbVie Inc., North Chicago, Illinois.

Molecular Cancer Research : MCR
|May 15, 2024
PubMed

Insights

Small-cell lung cancer (SCLC) with MYC/MYCN amplification shows sensitivity to mivebresib, a BET inhibitor. This suggests targeting chromatin landscapes could offer new SCLC treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Small-cell lung cancer (SCLC) has a high relapse rate after initial treatment.
  • Limited effective second-line therapies exist for SCLC.

Purpose of the Study:

  • To investigate the sensitivity of SCLC cell lines to the BET inhibitor mivebresib.
  • To explore the role of MYC family amplifications in SCLC response to epigenetic therapy.

Main Methods:

  • Utilized SCLC cell lines with varying MYC/MYCN amplification status.
  • Treated cell lines with mivebresib (a pan-BET bromodomain inhibitor).
  • Performed MYC/MYCN silencing and genome-wide binding analysis.

Main Results:

  • SCLC cell lines with MYC and MYCN amplification were more sensitive to mivebresib.
  • Silencing MYC/MYCN partially reversed mivebresib's antiproliferative effects.
  • Discovered unique enhancer and epigenetic preferences for MYC, MYCN, and MYCL1.

Conclusions:

  • Chromatin landscapes can dictate cell states and gene expression programs.
  • These programs confer sensitivity to epigenetic inhibitors like mivebresib in SCLC.
  • Suggests potential for targeting chromatin in SCLC treatment.

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