FLT mutants bind type II TKIs

Stable Identifier
R-HSA-9702510
Type
Reaction [binding]
Species
Homo sapiens
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Type II tyrosine kinase inhibitors bind to a hydrophobic region adjacent to the ATP-binding site that is only present in the inactive conformation of the receptor. As a consequence, type II inhibitors tend to be more effective against FLT3 with ITD than against FLT3 with activating mutations in the tyrosine kinase domain (reviewed in Klug et al, 2018; Larrosa-Garcia and Baer, 2017; Patnaik, 2018; Daver et al, 2019).

The following FLT3 mutants are sensitive to these type II tyrosine kinase inhibitors:

ponatinib:
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835N (Nguyen et al, 2017)
FLT3 Y591_V592insVDFREYEYDH (Nguyen et al, 2017)

quizartinib:
FLT3 E598_Y599insFDFREYE (Moore et al, 2012)
FLT3 L610_E611insLKWEFPRENL (Peschel et al, 2017)
FLT3 Y591_V592insVDFREYEYDH (Peschel et al, 2017)
FLT3 F621L (Williams et al, 2013)
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835H (Galanis et al, 2014)
FLT3 D835N (Galanis et al, 2014; Nguyen et al, 2017)

sorafenib:
FLT3 N676D (Albers et al, 2013)
FLT3 E598_Y599insFDFREYE (Moore et al, 2012)
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835N (Nguyen et al, 2017)

pexidartinib:
FLT3 F691L (Smith et al, 2015)

tandutinib:
FLT3 D835A (Clark et al, 2004)
FLT3 D835E (Clark et al, 2004)
FLT3 D835H (Clark et al, 2004)
FLT3 D835N (Clark et al, 2004)
FLT3 I836del (Clark et al, 2004)
FLT3 E598_Y599insFDFREYE (Kelly et al, 2002; Moore et al, 2012)

carbozantinib:
FLT3 L610_E611insLKWEFPRENL (Ko et al, 2019)

sunitinib:
FLT3 F663Q (Schittenhlem et al, 2006)
FLT3 F691L (Albers et al, 2013)
FLT3 Y842H (Albers et al, 2013)
FLT3 N676D (Albers et al, 2013)
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835N (Nguyen et al, 2017)
FLT3 Y591_V592insVDFREYEYDH (Schittenhelm et al, 2006)

Literature References
PubMed ID Title Journal Year
28077790 FLT3 activating mutations display differential sensitivity to multiple tyrosine kinase inhibitors

Levis, M, Nguyen, B, Williams, AB, Small, D, Brown, P, Li, L, Young, DJ, Ma, H

Oncotarget 2017
23392356 The secondary FLT3-ITD F691L mutation induces resistance to AC220 in FLT3-ITD+ AML but retains in vitro sensitivity to PKC412 and Sunitinib

Yu, C, Albers, C, Verbeek, M, Duyster, J, Leischner, H, Illert, AL, von Bubnoff, N, Peschel, C

Leukemia 2013
26108694 FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors

Shah, NP, Stecula, A, Smith, CC, Sali, A, Lin, K

Leukemia 2015
30651634 Targeting FLT3 mutations in AML: review of current knowledge and evidence

Schlenk, RF, Levis, MJ, Daver, N, Russell, NH

Leukemia 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
16990784 FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248)

Braziel, RM, McGreevey, L, Schittenhelm, MM, Griffith, DJ, O'Farrell, AM, Bainbridge, T, Heinrich, MC, Tyner, JW, Cherrington, JM, Yee, KW, Haley, AD, Town, A

Leukemia 2006
30862120 Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations-Possible Therapeutic Efficacy of Cabozantinib

Tien, HF, Ko, YC, Liu, ZH, Hu, CY, Chien, HF, Lin, LI, Ou, DL

Int J Mol Sci 2019
28522571 FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27Kip1 in acute myeloid leukemia

Jäkel, H, Duyster, J, Nachbaur, D, Götze, KS, Sill, H, Taschler, M, Hengst, L, Podmirseg, SR, Peschel, I

Haematologica 2017
15256420 Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518

Gilliland, DG, Lokker, NA, Curley, DP, Clark, JJ, Giese, NA, Yu, JC, Cools, J

Blood 2004
22354205 Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns

Pearson, AD, Avery, S, Workman, P, Faisal, A, Mair, D, Atrash, B, Blagg, J, Bavetsias, V, Linardopoulos, S, Mirabella, F, Valenti, M, Eccles, SA, Moore, AS, de Haven Brandon, A, Sun, C, Swansbury, J, Gonzalez de Castro, D, Raynaud, FI

Leukemia 2012
28576946 FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Baer, MR, Larrosa-Garcia, M

Mol. Cancer Ther. 2017
22858906 Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors

Nguyen, B, Brown, P, Li, L, Levis, M, Williams, AB, Leahy, D, Small, D

Leukemia 2013
29164965 The importance of FLT3 mutational analysis in acute myeloid leukemia

Patnaik, MM

Leuk. Lymphoma 2018
24227820 Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants

Levis, M, Small, D, Cortes, J, Ramachandran, A, Galanis, A, Rajkhowa, T, Ma, H

Blood 2014
12124172 CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)

Gilliland, DG, Boulton, CL, Kelly, LM, Duclos, N, Scarborough, RM, Li, J, Neuberg, D, Amaral, SM, Sullivan, CM, Hollenbach, S, Pandey, A, Lokker, NA, Williams, I, Apatira, M, Abe, K, Curley, DP, Giese, NA, Yu, JC

Cancer Cell 2002
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cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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