Fig. 3

The mechanism of action of existing drugs targeting KIT expression and mutations. In this figure we describe several inhibitors targeting KIT expression and function. Therapeutic strategies of TKIs targeting KIT mutations in gastrointestinal stromal tumors: fist-line therapy-Imatinib; second-line therapy-Sunitinib; third-line therapy-Regorafenib; fourth-line therapy-Ripretinib. Other new drugs targeting KIT mutations in gastrointestinal stromal tumors: Avapritinib, Larotrectinib, Entrectinib, Bezuclastinib, Carbozantinib, Sorafenib. The c-KIT-Hsp90Β-Apaf-1 complex inhibits the ubiquitination degradation of mutant KIT. Bortezomib binds to Cbl, destabilizing the c-KIT-Hsp90Β-Apaf-1 complex and releasing Apaf-1, and then KIT proteins are internalized and degraded in GIST cells. IPI-504, IPI-493, TAS-116, AT13387 and NVP-AUY922 are HSP90 inhibitors. HDAC inhibitors, SAHA and LBH589, attenuate the activity of HSP90 by acetylating on HSP90 gene. For Hh pathway, HHs, SMO and GI1/2 have their own inhibitors. PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-restricted inhibitor alpelisib all reducing GIST cell proliferation. TAT-N24 and the emerging PI3K or P55PIK inhibitors, such as Copanlisib, both inhibit NF -κB. BGJ398, PD173074 and nintedanib are FGFR inhibitor targeting FGFR1-4. ACK1 inhibitor AIM-100 or ACK1 siRNA inhibits ACK1. CS-1 and CS-2 are functioned as FTO inhibitors preventing KIT m6A mRNA demethylation. BBIs can reverse the transcription abnormalities of KIT gene which are induced by BRD4. Mithramycin A inhibits the TF, SP1, and HZ1 decreases the transcriptions of OSR1