Tumour Initiated Purinergic Signalling Can Promote Cardiomyocyte RBFOX1 Degradation and Increase the Risk for Developing Cardiotoxicity from DNA Damaging Anticancer Agents

It is well established tumour cells can secrete numerous signalling factors that affect distant normaltissues. What remains unresolved is if tumour secreted factors can initiate a signalling cascade thatcould render terminally differentiated cardiomyocytes susceptible to apoptosis, a feature ofchemotherapy-induced cardiotoxicity (CIC). Here we show in cancer patients from theMANTICORE trial, cumulative baseline plasma levels of the nucleoside inosine and its purinederivative hypoxanthine were predictive for mild or moderate cardiotoxicity. We found the Zn2+finger transcription factor ZNF281 can increase the synthesis and release of inosine andhypoxanthine (from cancer cells) by enhancing the cell membrane levels of several purinergicfactors. Mechanistically, we found that inosine or hypoxanthine can activate the A2A receptor oncardiomyocytes, activating CAMKII, which can phosphorylate the postnatal mRNA splicing factorRBFOX1, resulting in its caspase-dependent degradation. Loss of RBFOX1 reverts cardiomyocytesto a less mature state with features of open chromatin and susceptibility to DNA damage andapoptosis when treated with DNA intercalating or alkylating anticancer agents. In keeping,cardiomyocyte-specific RBFOX1-deficient mice developed cardiotoxicity and dilatedcardiomyopathy when treated with anthracyclines, compared to age/sex-matched controls. Thesefindings suggest that cumulative inosine and hypoxanthine levels may be a candidate biomarker topredict patient susceptibility to DNA damaging anti-cancer agents.