FLT mutants bind type I TKIs

Stable Identifier
R-HSA-9702508
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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Type I tyrosine kinase inhibitors bind to the ATP-binding site in the active conformation of the receptor. As a consequence, type I inhibitors are generally active both against FLT3 with ITD and 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 I tyrosine kinase inhibitors:

crenolanib:
FLT3 Y591_V592insVDFREYEYDH (Nguyen et al, 2017)
FLT3 D835A (Nguyen et al, 2017; Smith et al, 2015)
FLT3 D835E (Smith et al, 2015)
FLT3 D835F (Galanis et al, 2014; Nguyen et al, 2017; Smith et al, 2015)
FLT3 D835G (Nguyen et al, 2017; Smith et al, 2015)
FLT3 D835H (Smith et al, 2015)
FLT3 D835N (Galanis et al, 2014; Nguyen et al, 2017; Smith et al, 2015)
FLT3 D835V (Galanis et al, 2014; Smith et al, 2015)
FLT3 D835Y (Galanis et al, 2014; Nguyen et al, 2014; Smith et al, 2015)

midostaurin: FLT3 Y591_V592insVDFREYEYDH (Nguyen et al, 2017)
FLT3 Y572C (Frohling et al, 2007)
FLT3 V592G (Frohling et al, 2007)
FLT3 F621L (Williams et al, 2013)
FLT3 F691L (Albers et al, 2013)
FLT3 R834Q (Frohling et al, 2007)
FLT3 D835A (Nguyen et al, 2017)
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835H (Baker et al, 2013)
FLT3 D835Y (Baker et al, 2013; Knapper et al, 2006; Nguyen et al, 2017)
FLT3 Y842C (Williams et al, 2013)
FLT3 Y842H (Albers et al, 2013)
FLT3 A848P (Albers et al, 2013; von Bubnof et al, 2010)

gilteritinib:
FLT3 N676K (Tarver et al, 2020)
FLT3 D835F (Tarver et al, 2020)
FLT3 D835V (Tarver et al, 2020)
FLT3 D835Y (Mori et al, 2017; Tarver et al, 2020)
FLT3 I836del (Tarver et al, 2020)
FLT3 D839G (Tarver et al, 2020)
FLT3 Y842C (Tarver et al, 2020)
FLT3 N841I (Tarver et al, 2020)
FLT3 N841T (Tarver et al, 2020)
FLT3 N841Y (Tarver et al, 2020)
FLT3 L610_E611insLKWEFPRENL (Mori et al, 2017; Tarver et al, 2020)
FLT3 Y591_V592insVDFREYEYDH (Mori et al, 2017; Tarver et al, 2020)
FLT3 E598_Y599insFDFREYE (Mori et al, 2017; Tarver et al, 2020)
FLT3 E598_Y599insVDFREYE (Mori et al, 2017; Tarver et al, 2020)

lestaurtinib:
FLT3 Y591_V592insVDFREYEYDH (Knapper et al, 2006)
FLT3 D835A (Nguyen et al, 2017)
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835N (Nguyen et al, 2017)
FLT3 D835Y (Knapper et al,2006; Nguyen et al, 2017)
FLT3 E598_Y599insFDFREYE (Kim et al, 2005)
FLT3 L610_E611insLKWEFPRENL (Kim et al, 2005)
FLT3 Y591_V592insVDFREYEYDH (Nguyen et al, 2017)
FLT3 F621L (Williams et al, 2013) FLT3 Y842C (Williams et al, 2013)
FLT3 F691L (partial: Williams et al, 2013)

semaxanib:
FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL (Yee et al, 2002; Spiekermann et al, 2003)
FLT3 K602_W603insYEYDLK (Spiekermann et al, 2003)
FLT3 L601_K602insREYEDL (Spiekermann et al, 2003)
FLT3 Y591_V592insVDFREYEYDH (Spiekermann et al, 2003)
FLT3 D835Y (Spiekermann et al, 2003)

KW-2449:
FLT3 Y591_V592insVDFREYEYDH (Nguyen et al, 2017)
FLT3 E598_Y599insFDFREYE (Shiotsu et al, 2009)
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835N (Nguyen et al, 2017)

TTT-3002:
FLT3 Y591_V592insVDFREYEYDH (Nguyen et al, 2017)
FLT3 F691L (Ma et al, 2014a)
FLT3 V579A (Ma et al, 2014a)
FLT3 D835A (Nguyen et al, 2017)
FLT3 D835G (Nguyen et al, 2017)
FLT3 D835N (Nguyen et al, 2017)
FLT3 D835Y (Ma et al, 2014b; Nguyen et al, 2017)

linifanib: FLT3 Y591_V592insVDFREYEYDH (Hernandez-Davies et al, 2011)

Literature References
PubMed ID Title Journal Year
19541823 KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation

Shiotsu, Y, Kiyoi, H, Ishikawa, Y, Tanizaki, R, Shimizu, M, Umehara, H, Ishii, K, Mori, Y, Ozeki, K, Minami, Y, Abe, A, Maeda, H, Akiyama, T, Kanda, Y, Sato, Y, Akinaga, S, Naoe, T

Blood 2009
16868253 The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases

Knapper, S, Mills, KI, Gilkes, AF, Austin, SJ, Walsh, V, Burnett, AK

Blood 2006
26108694 FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors

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

Leukemia 2015
25060518 FLT3 kinase inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia

Ma, HS, Nguyen, B, Duffield, AS, Li, L, Galanis, A, Williams, AB, Brown, PA, Levis, MJ, Leahy, DJ, Small, D

Cancer Res. 2014
19318574 FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro

von Bubnoff, N, Engh, RA, Aberg, E, Sänger, J, Peschel, C, Duyster, J

Cancer Res. 2009
28576946 FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

Larrosa-Garcia, M, Baer, MR

Mol. Cancer Ther. 2017
23969938 Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia

Baker, SD, Zimmerman, EI, Wang, YD, Orwick, S, Zatechka, DS, Buaboonnam, J, Neale, GA, Olsen, SR, Enemark, EJ, Shurtleff, S, Rubnitz, JE, Mullighan, CG, Inaba, H

Clin. Cancer Res. 2013
18068628 Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles

Fröhling, S, Scholl, C, Levine, RL, Loriaux, M, Boggon, TJ, Bernard, OA, Berger, R, Döhner, H, Döhner, K, Ebert, BL, Teckie, S, Golub, TR, Jiang, J, Schittenhelm, MM, Lee, BH, Griffin, JD, Stone, RM, Heinrich, MC, Deininger, MW, Druker, BJ, Gilliland, DG

Cancer Cell 2007
15498859 Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival

Kim, KT, Baird, K, Ahn, JY, Meltzer, P, Lilly, M, Levis, M, Small, D

Blood 2005
23392356 The secondary FLT3-ITD F691L mutation induces resistance to AC220 in FLT3-ITD+ AML but retains in vitro sensitivity to PKC412 and Sunitinib

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

Leukemia 2013
28516360 Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia

Mori, M, Kaneko, N, Ueno, Y, Yamada, M, Tanaka, R, Saito, R, Shimada, I, Mori, K, Kuromitsu, S

Invest New Drugs 2017
30651634 Targeting FLT3 mutations in AML: review of current knowledge and evidence

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

Leukemia 2019
12796379 Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells

Spiekermann, K, Bagrintseva, K, Schwab, R, Schmieja, K, Hiddemann, W

Clin. Cancer Res. 2003
21471285 The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway

Hernandez-Davies, JE, Zape, JP, Landaw, EM, Tan, X, Presnell, A, Griffith, D, Heinrich, MC, Glaser, KB, Sakamoto, KM

Mol. Cancer Ther. 2011
12351406 SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase

Yee, KW, O'Farrell, AM, Smolich, BD, Cherrington, JM, McMahon, G, Wait, CL, McGreevey, LS, Griffith, DJ, Heinrich, MC

Blood 2002
22858906 Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors

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

Leukemia 2013
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Klug, LR, Kent, JD, Heinrich, MC

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

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

Blood 2014
29164965 The importance of FLT3 mutational analysis in acute myeloid leukemia

Patnaik, MM

Leuk. Lymphoma 2018
32040554 Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Tarver, TC, Hill, JE, Rahmat, L, Perl, AE, Bahceci, E, Mori, K, Smith, CC

Blood Adv 2020
24408321 TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo

Ma, H, Nguyen, B, Li, L, Greenblatt, S, Williams, A, Zhao, M, Levis, M, Rudek, M, Duffield, A, Small, D

Blood 2014
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cancer 162 malignant tumor, malignant neoplasm, primary cancer
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