Drug resistance of KIT mutants

Stable Identifier
Homo sapiens
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Activating mutations in the juxtamembrane domain of KIT are common in some cancers, including gastrointestinal stromal tumors, melanoma and acute myeloid leukemia (reviewed in Roskoski, 2018). These mutations are sensitive to inhibition with imatinib, which in 2001 was the first tyrosine kinase inhibitor approved for treatment of cancer (Demetri et al, 2002; Corless et al, 2011; reviewed in Zitvogel, 2016). Although highly successful in prolonging survival, imatinib-resistance develops in most patients due to appearance of secondary mutations, often in the ATP-binding pocket or in the activation loop of the kinase domain (Gajiwala et al, 2008; Serrano et al, 2019; reviewed in Roskoski, 2018; Napolitano and Vincenzi, 2019)
Literature References
PubMed ID Title Journal Year
22089421 Gastrointestinal stromal tumours: origin and molecular oncology

Barnett, CM, Corless, CL, Heinrich, MC

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

Roskoski, R

Pharmacol. Res. 2018
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
27030078 Immunological off-target effects of imatinib

Rusakiewicz, S, Ayyoub, M, Zitvogel, L, Routy, B, Kroemer, G

Nat Rev Clin Oncol 2016
30792534 Secondary KIT mutations: the GIST of drug resistance and sensitivity

Napolitano, A, Vincenzi, B

Br. J. Cancer 2019
12181401 Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors

Joensuu, H, Silberman, SL, Capdeville, R, Peng, B, Heinrich, MC, Singer, S, Roberts, PJ, Blanke, CD, von Mehren, M, Eisenberg, B, Fletcher, JA, Demetri, GD, Kiese, B, Corless, C, Silverman, SG, Fletcher, CD, Druker, BJ, Janicek, M, Dimitrijevic, S, Tuveson, DA, Van den Abbeele, AD

N. Engl. J. Med. 2002
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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