RU-302, a pan-TAM Inhibitor, Blocks Gas6-Inducible TAM Activation and Tumorigenicity
Posted On 2019-09-11
The TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous types I receptor tyrosine kinases (RTKs). They play an indispensable role in homeostasis and the resolution of inflammation under physiological conditions. Pathophysiologically, TAMs frequently overexpressed in a wide variety of human cancers that are associated with tumor progression and resistance to targeted therapeutics.
All three TAM receptors overexpress in a wide spectrum of human cancers. For example, overexpression of TAMs can drive conventional oncogenic signaling and survival pathways in both hematopoietic and solid cancers and metastasis. Gas6 also concomitantly overexpresses in many cancers.
A study from Stanley G. Kimani discovered and identified a pan TAM inhibitor RU-302. RU-302 is a pan TAM inhibitor that blocks the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Besides, RU-302 effectively blocks Gas6-inducible Axl receptor activation with a low micromolar IC50 and suppresses lung cancer tumor growth.
The authors evaluated in vivo efficacies of RU-302 using a murine NOD SCIDγ/human H1299 lung cancer xenograft model. As described before, SCID mice weres subcutaneously injected with human H1299 cells in the hind flanks until palpable tumors were present. Subsequently, mice were injected daily with vehicle and RU-302 as shown. RU-302 significantly decreased tumor volume, while body weights were not significantly different at both 100 mg/kg and 300 mg/kg. The authors used Western blotting to detect Phospho Axl and phospho Mertk levels in the primary tumors but could not be detected. Collectively, these studies support the further development of extracellular Gas6/TAM Ig1 inhibitors as anti-cancer therapeutics.
Kimani SG, et al. Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity. Sci Rep. 2017 Mar 8;7:43908.