Extracellular- , juxtamembrane- and kinase-domain mutants of KIT have been shown to signal through the STAT pathway, although the biological relevance or each STAT isoform varies between tumor types (Brizzi et al, 1999; Ning et al, 2001; Frost et al, 2002; Growney et al, 2005; Hara et al, 2017; Obata et al, 2017; Duensing et al, 2004; Bauer et al, 2007; Deberry et al, 1997; Ronnstrand, 2004). Although the pathway details haven't been examined in all cases, STAT pathway activation likely occurs through the recruitment of JAK2 and SRC family kinases, as is the case for the wild type receptor (reviewed in Lennartsson and Roonstrand, 2012).
KIT can be bound and inhibited by class I tyrosine kinase inhibitors including dovitinib and midostaurin, among others. Type I inhibitors bind in the ATP binding site of the active conformation and prevent activation of the kinase (reviewed in Roskoski, 2018; Abbbaspour Babaei et al, 2016).
Ripretinib is a example of a switch pocket inhibitor, a new type of class II tyrosine kinase inhibitors that is being developed for use against activation and drug resistant mutations in PDGFR and KIT (reviewed in Martin-Broto and Moura, 2020). Switch pocket inhibitors are type II tyrosine kinase inhibitors that force the activation loop (AL) into an inactive conformation, and are therefore active against AL mutants of KIT that are otherwise only sensitive to type I TKIs. Ripretinib is active against mutations affecting extracellular, juxtamembrane, ATP-binding pocket and activation loop domains and is thus the first inhibitor with pan-KIT inhibitory activity. Ripretinib has been successfully studied in TKI-refractory GIST (Smith et al, 2019).
Imatinib is approved for treatment of cancers carrying primary mutations in the KIT receptor. Imatinib binds and inhibits the inactive state of the receptor, including the conformation promoted by exon 11 mutations that relieve the auto-inhibition of the WT protein. Resistance to imatinib arises due to the polyclonal expansion of subpopulations bearing secondary KIT mutations in the ATP binding pocket or the activation loop of the protein (Serrano et al, 2019; reviewed in Roskoski, 2018; Klug et al, 2018; Corless et al, 2011).
Regorafenib is a type II tyrosine kinase inhibitor that is approved for treatment of advanced gastrointestinal stromal tumors with KIT mutations. Regorafenib is effective in imatinib-resistant tumors carrying secondary mutations in exon 14 (gatekeeper mutation), and most KIT secondary mutations encoded by exons 17 and 18 (the activation loop) (Demetri et al, 2013; Serrano et al, 2017, Serrano et al, 2019; reviewed in Roskoski, 2018; Klug et al, 2018; ).
Sunitinib is a class II tyrosine kinase inhibitor that is often used as a second line treatment in KIT-mutated cancers that develop resistance to imatinib (Heinrich et al, 2008; Serrano et al, 2017; reviewed in Roskoski, 2018; Corless et al, 2011).