Inhibitors of TGFβR1/ALK4/JNK3/Flt1 Kinases in Cynomolgus Macaques Lead to the Rapid Induction of Renal Epithelial Tumors.

Abstract

Two young cynomolgus macaques (Macaca fascicularis) given a small molecule kinase inhibitor (SCIO-120) via nasogastric intubation gavage, once-daily for 21\u2009days at 400\u2009mg/kg/day, developed an unusual epithelial proliferative process in the renal parenchyma. Morphological and immunohistochemical characterization of the lesions confirmed an invasive malignant epithelial neoplasm (carcinoma). A similar renal neoplasm was seen in a third macaque after a 14-day exposure to a second kinase inhibitor in the same chemical series (SCIO-974). Despite remarkably short latency periods, exposure to these kinase inhibitors was likely causally associated with the induction of the renal tumors, as renal carcinomas are exceedingly rare spontaneously in macaques. Both SCIO-120 and SCIO-974 were designed as potent TGFβR1 inhibitors (IC50s 37\u2009nM and 39\u2009nM, respectively). SCIO-120 and SCIO-974 inhibited additional kinases, most notably closely related ALK4 (IC50=34\u2009nM and 20\u2009nM, respectively), c-jun n-terminal kinase 3 (JNK3, IC50=10\u2009nM and 20\u2009nM, respectively), and Fms related tyrosine kinase 1 (29\u2009nM and 76\u2009nM, respectively). TGFβR1 has been specifically implicated in epithelial proliferative disorders, including neoplasia. Neither SCIO-120 nor SCIO-974 was genotoxic based on bacterial reverse mutation and/or clastogenicity screening assays. The rapid appearance of renal carcinomas in primates following short-term treatment with non-genotoxic kinase inhibitors is remarkable and suggests that the compounds had noteworthy tumor-enhancing effects, hypothetically linked to their TGFβR1 inhibition activity. These observations have implications for mechanisms of carcinogenesis and TGFβR1 biology.