Role and Significance of c-KIT Receptor Tyrosine Kinase in Cancer: A Review

Abstract

c-kit is a classical proto-oncogene that encodes a receptor tyrosine kinase (RTK) that responds to stem cell factor (SCF). C-KIT signaling is a critical regulator of cell proliferation, survival, and migration and is implicated in several physiological processes, including pigmentation, hematopoiesis and gut movement. Accumulating evidence suggests that dysregulated c-KIT function, caused by either overexpression or mutations in c-kit, promotes tumor development and progression in various human cancers. In this review, we discuss the most important structural and biological features of c-KIT, as well as insights into the activation of intracellular signaling pathways following SCF binding to this RTK. We then illustrate how different c-kit alterations are associated with specific human cancers and describe recent studies that highlight the contribution of c-KIT to cancer stemness, epithelial-mesenchymal transition and progression to metastatic disease in different experimental models. The impact of tyrosine kinase inhibitors in treating c-KIT-positive tumors and limitations due to their propensity to develop drug resistance are summarized. Finally, we appraise the potential of novel therapeutic approaches targeting c-KIT more selectively while minimizing toxicity to normal tissue.

Identification of Immunogenic cell death-Related Subgroups and Prognosis Model in lung adenocarcinoma

“…KIT is a tyrosine kinase growth factor receptor that plays a role in cell signaling in a variety of cell types. KIT activation mutations have been found in a variety of tumors (Miettinen and Lasota 2005) and KIT dysfunction caused by overexpression or mutation of KIT promotes the development and progression of various cancers (Sheikh, et al 2022). In one study, more than half of lung adenocarcinomas (61/95, 64%) were KIT positive, but KIT positive was not associated with tumor stage.…”

Therapeutic targeting of microtubule affinity‐regulating kinase 4 in cancer and neurodegenerative diseases

“…124 These inhibitors target the ATP-attaching site, whilst a small portion of the non-ATP competitive kinase inhibitors targets new allosteric sites. 130,131 However, the existing process for developing kinase inhibitors has developed from synthesizing analogs of several molecules to structure-based design methodologies, assisted via molecular docking, nuclear magnetic resonance spectroscopy, and crystallography. 132,133 Several inhibitors of MARK4 efficiently stop the overexpression of MARK4 activity.…”

“…Due to improved clinical efficacy, Food and Drug Administration (FDA) has approved several small‐molecule kinase inhibitors for clinical utilization and multiple understudies 124 . These inhibitors target the ATP‐attaching site, whilst a small portion of the non‐ATP competitive kinase inhibitors targets new allosteric sites 130,131 . However, the existing process for developing kinase inhibitors has developed from synthesizing analogs of several molecules to structure‐based design methodologies, assisted via molecular docking, nuclear magnetic resonance spectroscopy, and crystallography 132,133 …”

Ultrastructural features of tumor‐associated mast cells in parasympathetic paragangliomas (chemodectomas) of the neck

“…Mast cells (MCs) are a portion of innate immunity and their participation in the initiation of allergic reactions and the pathogenesis of allergic diseases has been well documented (Elieh Ali Komi & Bjermer, 2019). Their presence in TME gained attention for several reasons: (a) MCs express a wide range of receptors for cytokines, chemokines, complement, and immunoglobulins, that enables them to respond to various signals within TME (i.e., tumor cells produce stem cell factor, the key survival and growth factor of MCs, which acts through MC‐expressed c‐KIT) (Komi & Redegeld, 2020), (b) MCs upon activation degranulate and release three categories of mediators (preformed such as histamine, heparin, chymase, tryptase, de novo synthesized mediators, and later cytokines of which several are involved in tumor biology; Elieh Ali Komi et al, 2020), (c) promising results of tyrosine kinase inhibitors targeting C‐kit signaling and their effectiveness in different tumor types (Sheikh et al, 2022), (d) MCs accumulate in many tumors and their accumulation is associated to better or poor prognosis based on the tumor type (Dantas et al, 2017; Molin et al, 2002), (e) increased levels of MC specific mediators in serum of patients, which is associated to the prognosis or are suggested as markers for monitoring the chemotherapy (Goffredo et al, 2013; Ranieri et al, 2015; Sperr et al, 2009).…”