Imatinib-resistant KIT mutants do not bind imatinib

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Reaction [transition]
Homo sapiens
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Although most exon 11 mutations in the KIT receptor are senstive to inhibition with imatinib, many secondary mutations confer resistance to the drug. These mutations, which generally occur in exon 13 and 14, encoding the ATP-binding pocket or exon 17 and 18, encoding the activation loop, favor the active form of the receptor and are resistant to imatinib (Frost et al, 2002; Ma et al, 2002; Chen et al, 2004; Foster et al, 2004;Tamborini et al, 2006; Gajiwala et al, 2008; Maclean et al, 2008; Garner et al, 2014; Serrano et al, 2017; Serrano et al, 2019; reviewed in Roskoski et al, 2018; Napolitano and Vincenzi, 2019; Klug et al, 2018; Corless et al, 2011).

Literature References
PubMed ID Title Journal Year
16373716 Imatinib binding and cKIT inhibition is abrogated by the cKIT kinase domain I missense mutation Val654Ala

McLean, SR, Boshoff, C, Hartzoulakis, B, Gana-Weisz, M, Frow, R, Whelan, J, Selwood, D

Mol. Cancer Ther. 2005
15363456 Molecular basis of the constitutive activity and STI571 resistance of Asp816Val mutant KIT receptor tyrosine kinase

Griffith, R, Foster, R, Ferrao, P, Ashman, L

J. Mol. Graph. Model. 2004
22089421 Gastrointestinal stromal tumours: origin and molecular oncology

Barnett, CM, Corless, CL, Heinrich, MC

Nat. Rev. Cancer 2011
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
29704617 The role of small molecule Kit protein-tyrosine kinase inhibitors in the treatment of neoplastic disorders

Roskoski, R

Pharmacol. Res. 2018
12481435 Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant

Frost, MJ, Ferrao, PT, Hughes, TP, Ashman, LK

Mol. Cancer Ther. 2002
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
15342366 A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors

Raymond, AK, Choi, H, Frazier, ML, Wu, EF, Feig, BW, Hittelman, W, Ramdas, L, Velasco, MA, Patel, S, Oyedeji, CO, Pollock, RE, Prieto, VG, Benjamin, RS, Zhang, W, Burgess, MA, Hayes, KJ, Trent, JC, Chen, LL, Macapinlac, HA, Hunt, KK, Fuller, GN

Cancer Res. 2004
16751810 Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

Greco, A, Carbone, A, Ferrone, M, Pilotti, S, Casali, PG, Negri, T, Fermeglia, M, Lagonigro, MS, Gronchi, A, Pricl, S, Miselli, F, Tamborini, E, Pierotti, MA

Oncogene 2006
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
17363509 Resistance to c-KIT kinase inhibitors conferred by V654A mutation

Griffith, R, Odell, AF, Roberts, KG, Baleato, RM, Lyons, AB, Ashman, LK, Byrnes, EM

Mol. Cancer Ther. 2007
19164557 KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

Quenzer, T, Emmett, MR, Deshmukh, GD, Lunney, EA, English, JM, Wu, JC, Christensen, J, Molina, D, He, YA, Zhang, Y, Greig, MJ, Demetri, GD, Yu, X, Diehl, W, McTigue, M, Gajiwala, KS, DiNitto, JP, Wells, PA, Jacques, SL, Zou, A, Zhang, HM, Marshall, AG

Proc. Natl. Acad. Sci. U.S.A. 2009
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Heinrich, MC, Kent, JD, Klug, LR

Pharmacol. Ther. 2018
30792534 Secondary KIT mutations: the GIST of drug resistance and sensitivity

Napolitano, A, Vincenzi, B

Br. J. Cancer 2019
Normal reaction
Functional status

Loss of function of imatinib resistant KIT mutants [plasma membrane]

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