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MLCK Inhibition Induces Synthetic Lethality in MYC-Driven Cancer

Published:15 May 2025 DOI: 10.1016/j.canlet.2025.217803
Zhe Sun , Rui Wu , Xiaohui Liang , Tiezhu Shi , Yuan Zhang , Zelin Pan , Weidong Zhang , Xin Luan

Abstract

The dysregulation of MYC is widely implicated in human cancers, yet MYC remains an ‘undruggable’ target. Here, we performed a CRISPR-based loss-of-function screen focusing on kinases, most of which are ‘druggable,’ to identify genes essential for MYChigh but not MYClow cells. Using an isogenic pair of nonmalignant cells with and without ectopic MYC expression, we uncovered novel MYC synthetic lethal (MYC-SL) interactions, including Myosin Light-Chain Kinase (MLCK) as the most potent MYC-SL target. Inhibition of MLCK induced MYC-dependent cell death, significantly suppressing tumor growth in MYC-driven xenografts, the ApcMin/+ mouse model of colon cancer, and the MYC-transgenic hepatocellular carcinoma (HCC) model, without apparent toxicity. This cell death is attributed to selective DNA damage and p53-mediated apoptosis. Mechanistically, MYC activation promotes nuclear accumulation of myosin II at stalled replication forks, where it resolves replication stress and supports survival. MLCK inhibition disrupts myosin II activity, leading to unresolved replication stress, DNA damage, and activation of the p53-mediated apoptosis pathway. Our findings suggest that targeting MLCK offers a promising therapeutic strategy for MYC-driven cancers.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
2,3-Butanedione monoxime 57-71-6 C4H7NO2 421 suppliers $5.00-$4567.76
2,3-Butanedione monoxime 57-71-6 C4H7NO2 421 suppliers $5.00-$4567.76
2,3-Butanedione monoxime 57-71-6 C4H7NO2 421 suppliers $5.00-$4567.76
2,3-Butanedione monoxime 57-71-6 C4H7NO2 421 suppliers $5.00-$4567.76
(+/-)-BLEBBISTATIN 674289-55-5 C18H16N2O2 88 suppliers $17.00-$1960.00
(+/-)-BLEBBISTATIN 674289-55-5 C18H16N2O2 88 suppliers $17.00-$1960.00
(+/-)-BLEBBISTATIN 674289-55-5 C18H16N2O2 88 suppliers $17.00-$1960.00
(+/-)-BLEBBISTATIN 674289-55-5 C18H16N2O2 88 suppliers $17.00-$1960.00
2,3-Butanedione monoxime 57-71-6 C4H7NO2 - Inquiry
2,3-Butanedione monoxime 57-71-6 C4H7NO2 - Inquiry

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