Selective translation of ZNF281 as part of the integrated stress response system has therapeutic relevance for cardio-oncology

A well-recognized attribute of several common and standard cancer therapeutics is the development of cardiotoxicity. Although many anticancer agents appear to target a relatively select and distinct signaling pathway in the tumor, we hypothesized that several different classes of chemotherapeutics may converge into one central stress-sensing system in terminally differentiated cardiomyocytes. Here, we showed that anticancer intercalating/alkylating agents, tyrosine kinase inhibitors, or receptor inhibitors can converge and increase the selective and preferential translation of the transcription factor ZNF281 in cardiomyocytes. Cardiomyocyte-specific ZNF281-deficient mice were completely resistant to anthracycline-mediated cardiotoxicity (AIC), whereas cardiomyocyte-specific ZNF281-overexpressing mice had clinical features of cardiotoxicity. Inhibition of ZNF281 with ZIM, a first-of-its-kind small-molecule drug, completely prevented AIC, enhanced lung tumor regression, and prevented lung metastasis in a metastatic melanoma model. Induction of ZNF281, along with its downstream signaling cascade, was preserved in myocardial tissues from patients with AIC, indicating the translational potential of ZNF281 inhibition in alleviating cardiotoxicity resulting from chemotherapeutic treatments.