Table 1.
Main classes of drugs considered in GIST treatment.
| Class of drug | Drug | Mechanism of action | Reference |
|---|---|---|---|
| Tyrosine kinase inhibitors | Imatinib First line in GISTs |
TKI: It occupies the ATP-binding pocket of KIT/PDGFRA receptor and prevents substrate phosphorylation, thus inhibiting downstream signaling, cellular proliferation, and cell survival. | Quek and George4 |
| Sunitinib Second line in GISTs after imatinib failure |
Multitarget TKI: Similarly to imatinib, it occupies the ATP-binding pocket of KIT/PDGFRA receptor but inhibits also diverse tyrosine kinases including VEGFRs, FLT3, or RET. | Aparicio-Gallego et al5 | |
| Regorafenib Third line in GISTs after imatinib and sunitinib failure |
Multitarget TKI: similarly to sunitinib, it inhibits diverse tyrosine kinases (along with KIT/PDGFRA receptors), including FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, SAPK2, PTK5, and Abl. | Ettrich and Seufferlein6 | |
| Nilotinib | Second-generation KIT and PDGFRA inhibitor derived from imatinib, showing greater in vitro activity against BRC-ABL. Results from one phase I study, two phase II studies, and a compassionate use program showed preliminary evidence of clinical benefit in TKI-refractory GISTs. However, 2 randomized phase III studies have failed to demonstrate significant activity in either the first- or third-line setting. | Serrano and George7 | |
| Sorafenib | Multikinase inhibitor closely related to regorafenib, with activity against KIT and PDGFRA among several other kinases. Tested in GISTs after imatinib and sunitinib failure or even in fourth line. | Serrano and George7 | |
| Linsitinib | IR/IGF1R inhibitor, in trial for advanced WT GIST (trial NCT01560260). | NCI8 | |
| PI3K/AKT/mTOR inhibitors | They inhibit the PI3K/Akt/mTOR pathway, which is highly active in imatinib-resistant GISTs, as a result of secondary mutations in the KIT/PDGFRA kinase domains. Studies showed that mTOR inhibitors have limited success, which may be due to the activation of Akt that occurs following mTORC1 inhibition. Therefore, targeting PI3K or Akt, upstream of mTORC1, may result in a more efficient pathway inhibition. | Patel9 | |
| Heat-shock protein (HSP) inhibitors | HSPs are chaperone proteins that act on numerous so-called “client proteins,” including KIT and PDGFRA, stabilizing protein folding and assembly. | Songdej and von Mehren10 | |
| Demethylating agents | Agents capable of altering epigenetic states, including DNA methylation patterns and histone modification states. Hypermethylation is an attractive target with the aim of influencing tumor biology and overcoming therapy resistance. | Linnekamp et al11 |
ATP, adenosine triphosphate; GIST, gastrointestinal stromal tumor; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.