DISCUSSION
GIST, tumor, CRC, hepatotoxicity, decline in renal function, hypertension
TUMOR, MALIGNANCIES, HEPATOCELLULAR CARCINOMA, GIST, RENAL CELL CARCINOMA, HYPERTENSION, PATHOGENESIS, PREECLAMPSIA, THYROID CANCER
TKIs are becoming more commonly used for a number of malignancies. In the context of metastatic CRC, bevacizumab and regorafenib have established efficacy,The appearance of hypertension after initiating TKIs is reportedly associated with greater benefit in hepatocellular carcinoma, thyroid cancer, GIST, and renal cell carcinoma.Brivanib is a dual inhibitor of VEGF and FGF signaling pathways.Clinical bloodwork in our study demonstrated an association of brivanib‐associated hypertension with increased serum creatinine levels. While a decline in renal function has been reported in patients on TKIs,In order to gain an understanding of the pathogenesis of TKI‐induced hypertension, we also performed an exploratory metabolomic analysis. While large numbers of samples were not available for validation, some consistent metabolomic perturbations were observed. The experimental design involving serial samples represented a powerful approach to identifying treatment‐related changes in the metabolome. There were alterations in the circulating amino acid profile that are known to affect vascular physiology. For example, serine and threonine reportedly exert their influence on blood pressure via activation of the sympathetic nervous system and increasing the thickness of blood vessels by increasing their vascular tone.One interesting feature of brivanib‐associated hypertension was the increased levels of monosaccharides, including glucose, fructose, and mannose. This may partially be a result of impaired glycolysis. Indeed, in a study on the hepatotoxicity associated with TKIs, Paech et al. showed that TKIs are mitochondrial toxicants that inhibit glycolysis.Numerous studies have been performed on the metabolomic features accompanying preeclampsia.In conclusion, we found that the development of hypertension in CRC patients undergoing TKI administration was not associated with a survival benefit as seen in some other tumor types. Using GC–MS, we were able to identify a pattern of treatment‐related changes in the plasma metabolome that accompany hypertension. While the metabolomic studies were exploratory in nature, they have some common pathogenic features seen with preeclampsia. Further research is required to validate and confirm the identified metabolic profile.