Abstract 1677: Epithelial hyperplasia induced by a selective B-Raf inhibitor, WYE-130600
Authors: Besteman Elizabeth , Bienvenu Jean-Guy , Chaudhary Inder , Cukierski Mark , Marsh Billie , Surprenant Beth 
Published: February 2011

The Raf-MEK-ERK signaling pathway is critical for cell survival, growth, proliferation and tumorigenesis. The RAF kinases, ARAF, BRAF and CRAF, are essential signaling serine-threonine kinase proteins in the cascade. B-Raf mutations are frequent in human cancers suggesting small molecule B-Raf kinase inhibitors represent potential therapeutics for treatment of various cancers. The tolerability and limited safety of WYE-130600, a potent and highly selective inhibitor of B-Raf, was evaluated in investigative preclinical studies in dogs and rats. In dogs, a single dose of 10 mg/kg or 4 daily doses of 1 or 3 mg/kg WYE-130600 were administered orally, followed by a 7 day drug-free observation period after the last dose at 1 mg/kg. Clinical observations, body weight, food consumption, plasma concentrations, and clinical pathology were assessed at each dosage; limited microscopic examinations were conducted at 1 and 3 mg/kg. Dose-related dermal effects were observed at all dosages and progressed in severity; described as red discoloration (flushing) of the entire body, followed by swelling and subsequent dryness and desquamation of the dermis of the ears, eyelids, muzzle, prepuce, and anus. Alterations in clinical pathology parameters (increased neutrophils, monocytes and fibrinogen) consistent with an inflammatory response were observed. Microscopic cutaneous changes correlating to the clinical WYE-130600-related dermal effects included epidermal and hair follicle hyperplasia, hyperkeratosis, squamous metaplasia of the sebaceous glands, mixed cell inflammation and prominent dermal vessels in the haired skin. Partial recovery was evident at 1 mg/kg at the end of the 7-day observation period, when microscopic changes were limited to epithelial hyperplasia and mixed cell inflammation in the skin. In rats, WYE-130600 was administered orally at dosages of 15, 50 and 150 mg/kg, once daily for 4 days, followed by a 5-day observation period after the last dose. Evaluations for compound-related effects were based on clinical observations, body weight, food consumption and limited microscopic examinations. Clinical dermal effects at ≥50 mg/kg were limited to the skin of the feet. At 150 mg/kg, red discoloration of the skin of the feet progressed, as was noted in the dog, to swelling and a dry, scaly appearance. At 50 mg/kg, only dry, scaly skin of the feet were noted. Microscopically, epithelial hyperplasia and hyperkeratosis with mixed cell inflammation of the foot pads correlated with the clinical presentation. Atrophy of the hair follicles of the skin and inflammation/ hyperplasia of the nonglandular stomach were also noted at 150 mg/kg. In summary, epithelial hyperplasia occurred in rats and dogs and was attributed to this selective B-Raf inhibitor. The commonality of this lesion in both species suggests a potential for similar effects in humans.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1677.