Imatinib-resistant PDGFR mutants don't bind imatinib

Stable Identifier
Reaction [transition]
Homo sapiens
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PDGFRA mutations that are resistant to imatinib include point mutations and small deletion mutations centered around residue D842 (Heinrich et al, 2003; Corless et al, 2005); the gatekeeper mutation T674I (Cools et al, 2003; Lierman et al, 2006; Simon et al, 2008; Heinrich et al, 2012; Evans et al, 2017; Smith et al, 2019); S601P (Salemi et al, 2009) and Y288C (Ip et al, 2019) (reviewed in Roskoski, 2018; Klug et al, 2018). The resistance of PDGFRA Y288C is not shown in this failed reaction.

Literature References
PubMed ID Title Journal Year
29408302 The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders

Roskoski, R

Pharmacol. Res. 2018
12660384 A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

Marynen, P, Boogaerts, M, Griffin, JD, Galinsky, I, Cortes, J, Coutré, SE, Kantarjian, H, Schmid, J, Malone, J, Schrier, SL, Cools, J, Stover, EH, Wlodarska, I, Kutok, J, Rose, M, Verhoef, G, Vandenberghe, P, Gotlib, J, Gilliland, DG, Alam, R, Clark, J, Legare, RD, Cross, NC, Stone, R, Deangelo, DJ, Tefferi, A

N. Engl. J. Med. 2003
12522257 PDGFRA activating mutations in gastrointestinal stromal tumors

Corless, CL, Heinrich, MC, Singer, S, Griffith, DJ, Town, A, Haley, A, Duensing, A, McGreevey, L, Fletcher, JA, Demetri, GD, Joseph, N, Chen, CJ, Fletcher, CD

Science 2003
18234315 Primary resistance to imatinib in Fip1-like 1-platelet-derived growth factor receptor alpha-positive eosinophilic leukemia

Yousefi, S, Simon, D, Salemi, S, Simon, HU

J. Allergy Clin. Immunol. 2008
19210352 A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome

Scapozza, L, Simon, D, Salemi, S, Moretti, L, Simon, HU, Yousefi, S, Schmid, I

Allergy 2009
22665524 Sorafenib inhibits many kinase mutations associated with drug-resistant gastrointestinal stromal tumors

Fletcher, JA, Mariño-Enríquez, A, Heinrich, MC, Donsky, RS, Presnell, A, Griffith, DJ, McKinley, A, Liang, CW, Patterson, J, Taguchi, T

Mol. Cancer Ther. 2012
16645167 Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant

Marynen, P, Boogaerts, M, Folens, C, Vandenberghe, P, Mentens, N, Scheers, W, Lierman, E, Cools, J, Van Miegroet, H, Stover, EH

Blood 2006
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Heinrich, MC, Kent, JD, Klug, LR

Pharmacol. Ther. 2018
29093181 A precision therapy against cancers driven by KIT/PDGFRA mutations

Heinrich, MC, Zhang, Y, Hodous, BL, Shutes, A, Lengauer, C, Evans, EK, Kohl, N, Wolf, B, Schöffski, P, Zhu, XJ, Kim, JL, Gebreyohannes, YK, Gardino, AK, Wozniak, A, DiPietro, L, Lydon, N, Wilson, K, Brooijmans, N, Schmidt-Kittler, O, Boral, A, Miller, S, LaBranche, TP, Deangelo, DJ, Davis, A, Guzi, T, Wilson, D

Sci Transl Med 2017
15928335 PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib

Shiraga, S, McGreevey, L, Schroeder, A, Corless, CL, Heinrich, MC, Harrell, P, Morich, J, Bainbridge, T, Town, A, Griffith, D

J. Clin. Oncol. 2005
31085175 Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants

Hood, MM, Gupta, A, Su, Y, Ensinger, CL, Caldwell, TM, Bulfer, SL, Heinrich, MC, Al-Ani, G, Ahn, YM, Patt, WC, Janku, F, Turner, BA, Ruiz-Soto, R, Leary, CB, Abdul Razak, AR, Yates, K, Town, A, Rosen, O, Wise, SC, Vogeti, L, Telikepalli, H, Rutkoski, TJ, Vogeti, S, Smith, BD, Flynn, DL, Chun, L, Lu, WP, Kaufman, MD, McKinley, A

Cancer Cell 2019
Normal reaction
Functional status

Loss of function of imatinib-resistant PDGFR mutants [plasma membrane]

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