P95Effects of dabrafenib and trametinib, cancer therapies that target BRaf and MEK, on cardiac signalling

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Abstract

Background: The extracellular signal-regulated kinase (ERK1/2) cascade is implicated in cardioprotection and cardiac hypertrophy. Enhanced ERK1/2 signalling is associated with cancer, particularly in melanoma in which ~50% of cancers result from mutations of the upstream kinase BRaf that signals through MEK to ERK1/2. Inhibitors of BRaf (e.g. dabrafenib, DAB) and/or MEK (trametinib, TRAM) are in clinical use as cancer therapies. Early studies failed to identify BRaf in the heart and, whilst BRaf and MEK inhibitors are known to affect cardiac function, their molecular effects remain to be established. Materials and methods. Expression of BRaf was assessed in neonatal rat cardiomyocytes and adult rat hearts by immunoblotting. BRaf activities were measured following immunoprecipitation. Adult rat hearts were perfused in the Langendorff mode under control conditions, with DAB or TRAM alone, with fibroblast growth factor (FGF) or with FGF in the presence of DAB or TRAM. Signalling through the ERK1/2 cascade and potential off-target effects on the cytoprotective Akt pathway were assessed by immunoblotting. Results and discussion. BRaf protein was detected in extracts from adult rat hearts or cardiomyocytes as a doublet of ~90 kDa (predicted 89 kDa). Activity assays confirmed that BRaf has high basal activity that was further increased by peptide growth factors. Perfusion of rat hearts with DAB inhibited baseline phosphorylation (i.e. activation) of MEK and ERK1/2, whilst TRAM inhibited baseline activation of ERK1/2. These data suggest that BRaf activity is required for basal ERK1/2 activation in the heart. Both inhibitors prevented activation of ERK1/2 and downstream kinases (p90 RSK, p70 S6K) by FGF further indicating that growth factor signalling is mediated by BRaf in the heart. Interestingly, whilst DAB inhibited basal Akt phosphorylation, TRAM enhanced Akt signalling in control and FGF-perfused hearts. Conclusions. BRaf is expressed in cardiomyocytes and adult hearts at significant levels, has high basal activity and is activated by peptide growth factors. BRaf and MEK inhibitors in use for cancer therapy suppress basal and growth factor induced activation of ERK1/2 signalling suggesting that they are likely to have cardiotoxic effects. However, potentially damaging inhibition of ERK1/2 signalling by TRAM may be mitigated in part by enhanced cytoprotection via Akt if this pathway is not compromised.

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