c-KIT Has a Tumor-Suppressive Role via Induction of Apoptosis

The receptor tyrosine kinase c-KIT is a proto-oncogene that is subject to dysregulation and gain-of-function mutations and amplifications that promote tumorigenesis in a variety of tumor types. In other tumor types, including neuroblastoma, c-KIT is associated with differentiation and a good prognosis, but the molecular basis for these opposing effects has not been elucidated. A number of dependence receptors have been identified as activating their canonical signaling pathway in the presence of their ligand, but triggering apoptosis in the absence of their ligand, via an alternative pathway that is independent of the classic intrinsic and extrinsic apoptotic pathways. This proapoptotic activity suggests that these dependence receptors may act as tumor suppressors. Wang and colleagues sought to determine if c-KIT could act as a dependence receptor and if this would explain its nononcogenic effects. Indeed, c-KIT expression triggered apoptotic cell death in vitro, with a kinase dead mutant having the strongest proapoptotic effect. The proapoptotic effect of c-KIT appeared to be somewhat masked by the pro-growth effects of c-KIT kinase activity. The induction of apoptosis by c-KIT was caspase-dependent and inhibited by the c-KIT ligand SCF, supporting a role for c-KIT as a dependence receptor. In a melanoma xenograft model, inducible expression of kinase-dead c-KIT triggered apoptosis and suppressed tumor growth. Further, inhibition of SCF induced apoptosis in cells expressing wild-type c-KIT, suggesting that blocking the SCF–c-KIT interaction might be a strategy to activate the dependence receptor function of c-KIT without activation of its oncogenic kinase activity. In a colon cancer xenograft model, overexpression of the c-KIT extracellular domain, which interacts with SCF to prevent binding to the membrane-bound c-KIT, slowed tumor growth. Collectively, these findings suggest that, in addition to its oncogenic kinase activity, c-KIT may have a tumor-suppressive role as dependence receptor, suggesting the potential for therapeutic inhibition of the SCF–c-KIT interaction.

Wang H, Boussouar A, Mazelin L, Tauszig-Delamasure S, Sun Y, Goldschneider D, et al. The proto-oncogene c-Kit inhibits tumor growth by behaving as a dependence receptor. Mol Cell 2018 Sep 25 [Epub ahead of print].

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