Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation
In cancer, clinicians continue to struggle with patients not responding to targeted treatments, despite the presence of the potential drug target. It is, therefore, of utmost importance to understand how a drug is metabolized as a basis for improved drug selection and prevention of undesired effects. Early in the drug development process, circulating metabolites may provide the desired answers and markers to understand this mechanism of action.
Moreover, access to human tumor tissue is often limited, and biomarkers in minimal invasive matrices, like blood plasma, are favored. The use of preclinical models, such as mouse xenografts, for the identification of biomarkers that can be translated into clinical settings would further facilitate pharmacological studies.
In a recent study led by Dr. Florence Reynaud from the Institute of Cancer Research in London, UK, the researchers investigated a novel cancer drug in preclinical mouse models and evaluated its performance in early clinical trials. This is already the third study by this group proving the successful application of targeted metabolomics to identify drug-related changes in preclinical samples that can be translated to clinical ones. In the current study, the team deals with a multi-target AGC kinase inhibitor; the previous studies were dedicated to a PI3K inhibitor and a MEK inhibitor, respectively.
The multi-AGC kinase inhibitor AT13148 affected plasma levels of 45 metabolites in non-tumor bearing mice compared to untreated mice, whereas in mice with human tumor xenografts, surprisingly, no robust signature could be revealed. Indeed, 44 out of these 45 metabolites were confirmed to be altered in plasma from advanced cancer patients treated with AT13148 in a Phase I dose-escalation clinical study. A gene-metabolite network analysis showed a strong link to an activated nitric oxide synthase (NOS) pathway. This is in line with the observed decreased plasma levels of asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, and simultaneous increased hypotension in patients at higher doses. The underlying mechanism for the clinically observed phenotype can be explained with an AT13148-triggered NOS activation leading to an enhanced production of the vasodilator NO and, thus, leading to hypotension.
Though circulating metabolites have been shown to be promising pharmacodynamic or even predictive markers translatable from preclinical to clinical trials in previous studies with single-target drugs, this seems to be especially challenging in the case of multi-target drugs. However, in the present study, it was demonstrated that changes in circulating metabolite levels induced by a multi-AGC kinase inhibitor in mice and patients may contribute to a better understanding of its mechanism of action.
If you are interested in more examples on how metabolic profiling can be applied in pharmacological studies, please visit the literature section on pharmacology on our webpage.
Pal A, Asad Y, Ruddle R, et al.: Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation. (2020) Metabolomics | https//doi.org/10.1007/s11306-020-01676-0