Abstract A227: The involvement of wild-type KIT overexpression in colon cancers.

Abstract

Abstract Abnormal signaling through receptor tyrosine kinase (RTK) moieties is crucial in tumor progression and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, the functional role of SCF-dependent KIT activation is barely understood in colon cancer pathogenesis. In this study, we aimed to determine the conditions and roles of WT-KIT activation in colon cancer tumorigenesis. We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF treatment, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also demonstrated that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC-δ was activated. We also showed that activated PKC-δ directly binds to SCF bound WT-KIT, facilitating the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-δ and that expression of KIT is correlated with poor patient survival (P = 0.004). We herein for the first time demonstrated that continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-δ-mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A227. Citation Format: Wonkyu Kim, Misun Park, Hogeun Kim. The involvement of wild-type KIT overexpression in colon cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A227.