Regorafenib induces rapid and reversible changes in plasma nitric oxide and endothelin-1.
BACKGROUND
Hypertension is a toxicity of antiangiogenic therapies and a possible biomarker that identifies patients with superior cancer outcomes. Understanding its mechanism will aid in treatment and could lead to the development of other biomarkers for predicting toxicity and anticancer efficacy. Recent evidence implicates nitric oxide (NO) suppression and endothelin-1 (ET-1) stimulation as potential mechanisms leading to antiangiogenic therapy-induced hypertension. The aim of this study was to evaluate the effects of regorafenib, a novel broad-spectrum kinase inhibitor with activity against multiple targets, including vascular endothelial growth factor receptor 2 inhibition, on NO and ET-1 levels.


METHODS
Regorafenib was administered to 32 subjects with gastrointestinal stromal tumor on a 3-week-on, 1-week-off basis. Plasma levels of NO and ET-1 were measured at baseline, 2, 4, and 6 weeks of therapy. Data analysis was by Wilcoxon rank-sum and paired t-tests.


RESULTS
Twenty subjects (63%) developed regorafenib-induced hypertension. Two weeks after starting regorafenib therapy, plasma ET-1 levels increased (25% increase, P < 0.05) and NO was suppressed (20% decrease, P < 0.05). These normalized after 1-week washout but ET-1 rose again by 30% (P < 0.05) and NO fell by 50% (P < 0.05) after restarting regorafenib.


CONCLUSIONS
These findings indicate that regorafenib induces a coordinated and reversible suppression of NO and stimulation of ET-1. Whether NO and ET-1 might predict therapeutic efficacy in these patients requires further study.
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Massachusetts, USA.
Nilka
N
de Jesus-Gonzalez
Emily
E
Robinson
Radostin
R
Penchev
Margaret
M
von Mehren
Michael C
MC
Heinrich
William
W
Tap
Qian
Q
Wang
George
G
Demetri
Suzanne
S
George
Benjamin D
BD
Humphreys
D020533:Angiogenesis Inhibitors / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood*; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood*; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D019332:Endothelin-1; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D009569:Nitric Oxide