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MLCK inhibition induces synthetic lethality in MYC-driven cancer

Zhe Sun1, Rui Wu1, Xiaohui Liang1

  • 1Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Cancer Letters
|May 17, 2025
PubMed

Insights

Researchers identified Myosin Light-Chain Kinase (MLCK) as a target for MYC-driven cancers. Inhibiting MLCK triggers cancer cell death by inducing DNA damage and apoptosis, offering a potential new therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MYC dysregulation is a key driver in many human cancers.
  • MYC is considered an 'undruggable' target for cancer therapy.
  • Identifying druggable targets synthetic lethal with MYC is crucial.

Purpose of the Study:

  • To identify novel synthetic lethal interactions with MYC using a kinase-focused CRISPR screen.
  • To evaluate Myosin Light-Chain Kinase (MLCK) as a potential therapeutic target for MYC-driven cancers.

Main Methods:

  • Conducted a CRISPR-based loss-of-function screen in isogenic cells with and without ectopic MYC expression.
  • Utilized MYC-high and MYC-low cell models to identify synthetic lethal interactions.
  • Inhibited MLCK in various preclinical cancer models (xenografts, ApcMin/+, MYC-transgenic HCC).

Main Results:

  • Identified MLCK as a potent MYC synthetic lethal target.
  • MLCK inhibition induced MYC-dependent cell death via DNA damage and p53-mediated apoptosis.
  • MLCK inhibition suppressed tumor growth in multiple MYC-driven cancer models without apparent toxicity.

Conclusions:

  • Targeting MLCK is a promising therapeutic strategy for MYC-driven cancers.
  • MLCK inhibition disrupts myosin II activity at replication forks, leading to unresolved replication stress and apoptosis.
  • This approach offers a potential avenue for treating cancers with high MYC expression.

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