Kinome and transcriptome profiling reveal broad and distinct activities of erlotinib, sunitinib, and sorafenib in the mouse heart and suggest cardiotoxicity from combined STAT and EGFR inhibition

We administered clinically relevant doses of sorafenib, sunitinib (cardiotoxic multi-targeted kinase inhibitors) or erlotinib (a cardiosafe EGFR inhibitor) to mice daily for two weeks. We then compared the effects of these three kinase inhibitors on the cardiac transcriptome using RNAseq and the cardiac kinome using multiplexed inhibitor beads coupled with mass spectrometry. We found unexpectedly broad molecular effects of all three kinase inhibitors, suggesting that target kinase selectivity does not define either the molecular response or the potential for cardiotoxicity. Using in vivo drug administration and primary cardiomyocyte culture, we also show that the cardiosafety of erlotinib treatment may result from upregulation of the cardioprotective STAT3 pathway, as co-treatment with erlotinib and a STAT inhibitor decreases cardiac contractile function and cardiomyocyte fatty acid oxidation. 12 total murine heart samples: (3) water control, (3) 14 day sunitinib treatment, (3) 14 day sorafenib treatment, (3) 14 day erlotinib treatment