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Updated: Jul 26, 2026
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
A high-content screen identifies the vulnerability of MYC-overexpressing cells to dimethylfasudil
Jing Zhang1, Shenqiu Zhang1, Qiong Shi1
1Anticancer Biosciences and the J. Michael Bishop Institute of Cancer Research, Chengdu, China.
Abstract:
A synthetic lethal effect arises when a cancer-associated change introduces a unique vulnerability to cancer cells that makes them unusually susceptible to a drug's inhibitory activity. The synthetic lethal approach is attractive because it enables targeting of cancers harboring specific genomic or epigenomic alterations, the products of which may have proven refractory to direct targeting. An example is cancer driven by overexpression of MYC. Here, we conducted a high-content screen for compounds that are synthetic lethal to elevated MYC using a small-molecule library to identify compounds that are closely related to, or are themselves, regulatory-approved drugs. The screen identified dimethylfasudil, a potent and reversible inhibitor of Rho-associated kinases, ROCK1 and ROCK2. Close analogs of dimethylfasudil are used clinically to treat neurologic and cardiovascular disorders. The synthetic lethal interaction was conserved in rodent and human cell lines and could be observed with activation of either MYC or its paralog MYCN. The synthetic lethality seems specific to MYC overexpressing cells as it could not be substituted by a variety of oncogenic manipulations and synthetic lethality was diminished by RNAi-mediated depletion of MYC in human cancer cell lines. Collectively, these data support investigation of the use of dimethylfasudil as a drug that is synthetic lethal for malignancies that specifically overexpress MYC.
Insights
Researchers discovered a new synthetic lethal drug, dimethylfasudil, that targets cancer cells overexpressing the MYC gene. This finding offers a promising therapeutic strategy for specific MYC-driven malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Synthetic lethality exploits cancer-specific vulnerabilities for targeted therapy.
- Overexpression of MYC is a driver in various cancers, presenting a therapeutic challenge.
- Identifying drugs that induce synthetic lethality in MYC-driven cancers is a key goal.
Purpose of the Study:
- To screen for compounds that exhibit synthetic lethality with elevated MYC expression.
- To identify regulatory-approved drugs or close analogs with this synthetic lethal activity.
- To validate the specificity and conservation of the synthetic lethal interaction.
Main Methods:
- High-content screening of a small-molecule library against MYC-overexpressing cells.
- Assaying for compounds that induce cell death specifically in the presence of elevated MYC.
- Utilizing rodent and human cell lines, including MYCN paralog activation and RNAi-mediated MYC depletion.
- Testing specificity against various oncogenic manipulations.
Main Results:
- Dimethylfasudil, a ROCK1/ROCK2 inhibitor, was identified as a synthetic lethal compound with elevated MYC.
- The synthetic lethal effect was observed in both rodent and human cell lines and with MYCN activation.
- Specificity was demonstrated as the effect was not replicated by other oncogenic alterations and was reduced by MYC depletion.
- Dimethylfasudil analogs are already in clinical use for other conditions.
Conclusions:
- Dimethylfasudil demonstrates synthetic lethality specifically in MYC-overexpressing cancer cells.
- This finding supports the potential of dimethylfasudil as a targeted therapy for MYC-driven cancers.
- Further investigation into dimethylfasudil for treating MYC-driven malignancies is warranted.
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