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.
Highlights
We assayed more than 2700 compounds for activity that recapitulated the cellular contexts under which cells could not survive with high levels of the MYC oncogene
We generated a pair of isogenic cell lines, RPE-NEO and RPE-MYC, by engineering human retinal pigment epithelial (RPE) cells to ectopically express a neomycin resistance gene and the MYC oncogene, respectively
Events were considered positive for synthetic lethality with MYC when cell death was present in RPE-MYC cells, but absent in RPE-NEO cells
Summary
Synthetic lethal targeting of tumors overexpressing MYC holds promise for attacking aggressive malignancies. We describe a synthetic lethal interaction between dimethylfasudil and overexpression of MYC. This novel synthetic lethal interaction points toward an opportunity for synthetic lethality with a molecule likely to harbor favorable drug-like properties that enable systemic use
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