KIT mutants bind type II TKIs

Stable Identifier
Reaction [binding]
Homo sapiens
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Imatinib and other type II TKIs bind to the inactive form of KIT at a hydrophobic pocket near the ATP binding cleft that is not present in the active form of the receptor (Liu and Gray, 2006; Zhang et al, 2009; reviewed in Roskoski, 2018; Klug et al, 2018). Sensitivity of KIT mutants to type II inhibitors varies. Many juxtamembrane domain mutants, which favor the non-autoinhibited, DFG out inactive state, bind imatinib and other type II TKIs (Garner et al, 2014; Serrano et al, 2017; Debiec-Rychter et al, 2004; Serrano et al, 2019; reviewed in Roskoski, 2018; Klug et al, 2018; Corless et al, 2011). Primary extracellular mutations in KIT are only partially sensitive to imatinib (Debiec-Rychter et al, 2004; reviewed in Corless et al, 2011).
Literature References
PubMed ID Title Journal Year
19104514 Targeting cancer with small molecule kinase inhibitors

Zhang, J, Yang, PL, Gray, NS

Nat. Rev. Cancer 2009
22089421 Gastrointestinal stromal tumours: origin and molecular oncology

Barnett, CM, Corless, CL, Heinrich, MC

Nat. Rev. Cancer 2011
16783341 Rational design of inhibitors that bind to inactive kinase conformations

Liu, Y, Gray, NS

Nat. Chem. Biol. 2006
25239608 Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients

Anjum, R, Heinrich, MC, Ketzer, J, Bauer, S, Zhu, M, Zhou, T, Serrano, C, Song, Y, Fletcher, JA, Schrock, A, Ning, Y, Eilers, G, Wardwell, S, Gozgit, JM, Kohlmann, A, Garner, AP, Rivera, VM, Vodala, S, Clackson, T, Wang, F

Clin. Cancer Res. 2014
28478525 Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Morales-Barrera, R, Carles, J, Suárez, C, García-Valverde, A, Olivares, D, Valverde, C, George, S, Serrano, C

Target Oncol 2017
29704617 The role of small molecule Kit protein-tyrosine kinase inhibitors in the treatment of neoplastic disorders

Roskoski, R

Pharmacol. Res. 2018
15010069 Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group

Sciot, R, Debiec-Rychter, M, van Glabbeke, M, Stul, M, Dumez, H, van Oosterom, AT, EORTC Soft Tissue and Bone Sarcoma Group, -, Verweij, J, Judson, I, Hagemeijer, A, Brown, M, Vranck, H, Wasag, B, Dimitrijevic, S, Scurr, M

Eur. J. Cancer 2004
30792533 Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours

Heinrich, MC, Ketzer, J, Bauer, S, Zhu, M, Presnell, A, Raut, CP, George, S, Mannan, AM, Serrano, C, Yu, C, Sicinska, E, Tao, DL, Rubin, BP, Fletcher, JA, Mariño-Enríquez, A, Demetri, GD, Eilers, G, Czaplinski, JT, McKinley, A

Br. J. Cancer 2019
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Heinrich, MC, Kent, JD, Klug, LR

Pharmacol. Ther. 2018
Normal reaction
Functional status

Gain of function of type II TKI sensitive KIT mutants [plasma membrane]

Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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