Baseline cumulative plasma inosine and hypoxanthine levels greater than 6 μM predicted mild or moderate chemotherapy-induced cardiotoxicity in breast cancer patients.
Observational (n=22)
Do elevated baseline cumulative plasma inosine and hypoxanthine levels predict susceptibility to chemotherapy-induced cardiotoxicity in breast cancer patients?
Tumour-secreted inosine and hypoxanthine promote cardiomyocyte RBFOX1 degradation, reverting cells to a less mature state and increasing susceptibility to chemotherapy-induced cardiotoxicity, serving as a potential predictive biomarker.
p-value: p=0.036
It is well established tumour cells secrete signalling factors affecting distant normal tissues. What remains unresolved is whether these factors initiate a signalling cascade rendering terminally differentiated cardiomyocytes susceptible to apoptosis, a feature of chemotherapy-induced cardiotoxicity (CIC). Here we show in MANTICORE trial cancer patients, cumulative baseline plasma levels of the nucleoside inosine and its derivative hypoxanthine predict cardiotoxicity. We found the Zn2+ finger transcription factor ZNF281 increases synthesis and release of inosine and hypoxanthine, which bind the A2A receptor on cardiomyocytes, activating CAMKIIδ which phosphorylates the postnatal mRNA splicing factor RBFOX1, resulting in its caspase-dependent degradation. RBFOX1 loss reverts cardiomyocytes to a less mature state with open chromatin and susceptibility to DNA damage, apoptosis or CIC, when treated with DNA intercalating or alkylating anticancer agents. These findings suggest cumulative inosine and hypoxanthine levels may be a biomarker predicting patient susceptibility to DNA damaging anti-cancer agents. Chemotherapy-induced cardiotoxicity (CIC) is an adverse condition associated with several DNA damaging chemotherapeutics. Here, the authors discover that tumour ZNF281-mediated increase of purinergic signalling factors inosine and hypoxanthine promotes RBFOX1 degradation in cardiomyocytes, increasing the risk for developing CIC.
Tejay et al. (Fri,) conducted a observational in Breast cancer (chemotherapy-induced cardiotoxicity) (n=22). Cumulative plasma inosine and hypoxanthine levels > 6 μM vs. Cumulative plasma inosine and hypoxanthine levels < 6 μM was evaluated on Mild or moderate cardiotoxicity (p=0.036). Baseline cumulative plasma inosine and hypoxanthine levels greater than 6 μM predicted mild or moderate chemotherapy-induced cardiotoxicity in breast cancer patients.