Liganded-ALK dimer binds type I ALK-binding TKIs

Stable Identifier
Reaction [binding]
Homo sapiens
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ALK can be bound and inhibited by type I tyrosine kinase inhibitors. Type I inhibitors bind in the ATP-binding site of the active conformation and prevent activation of the kinase (reviewed in Klug et al 2018; Roskoski, 2013). Crizotinib was one the first ALK inhibitors to be approved for use in ALK+ cancers (reviewed in Rodig et al, 2010; Ou et al, 2011; Gambacorti et al, 2011). Accumulation of secondary mutations leads to acquired crizotinib resistance and has prompted the development of second-and third generation inhibitors such as ceritinib, alectinib, brigatinib and lorlatinib, among others (Ou et al, 2014; Ou et al, 2016; Shaw et al, 2015; Ceccon et al, 2013; Ceccon et al, 2015; Zhang et al, 2016; Shaw et al, 2014; Recondo et al, 2020; Galkin et al, 2006; reviewed in Della Corte et al, 2018). Resistance to ALK inhibitors has also been reported in the context of bypass tracks including activation of pim1 in neuroblastoma, IL10R-STAT3 in ALCL and EGFR in NSCLC (Trigg et al, 2019, Prokoph et al, 2020, Lin et al, 2017).
Literature References
PubMed ID Title Journal Year
24736079 Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib

Azada, M, Ignatius Ou, SH, Klempner, SJ, Herman, JM, Ali, SM, He, J, Casey, C, Siwak-Tapp, C, Miller, VA, Hsiang, DJ, Kain, TS

J Thorac Oncol 2014
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Heinrich, MC, Kent, JD, Klug, LR

Pharmacol. Ther. 2018
21345110 Crizotinib in anaplastic large-cell lymphoma

Messa, C, Pogliani, EM, Gambacorti-Passerini, C

N. Engl. J. Med. 2011
23201355 Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition

Roskoski, R

Pharmacol. Res. 2013
17185414 Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK

Melnick, JS, Ding, P, Liu, Y, Li, N, Hood, TL, Wan, Y, Li, L, Schultz, PG, Warmuth, M, Kim, S, Steensma, R, Galkin, AV, Chopiuk, G, Gray, NS, Sun, F, Jiang, J, Xia, G

Proc. Natl. Acad. Sci. U.S.A. 2007
23239810 Crizotinib-resistant NPM-ALK mutants confer differential sensitivity to unrelated Alk inhibitors

Ceccon, M, Mologni, L, Scapozza, L, Bisson, W, Gambacorti-Passerini, C

Mol. Cancer Res. 2013
32573700 IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma

Chiarle, R, Schleiermacher, G, Lambilliotte, A, Forde, SD, Lobello, C, Pacquement, H, Attarbaschi, A, Probst, NA, Prokoph, N, Malik, V, Barbieri, I, Gambacorti-Passerini, C, Sharma, GG, Klapper, W, Liang, HC, Mologni, L, Woessmann, W, Pospisilova, S, Wang, Q, Pervez, S, Ducray, SP, Geoerger, B, Landman-Parker, J, Turner, SD, Montes-Mojarro, IA, Monahan, JM, Matthews, JD, Kenner, L, Luan, SL, Merkel, O, Vassal, G, Jauch, R, Burke, GAA, Larose, H, Bahnsen, K, Janíková, A, Brugières, L, Lee, LC, Karaca-Atabay, E

Blood 2020
26464158 ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression

Klempner, SJ, Ali, SM, Ou, SH, Milliken, JC, Miller, VA, Azada, MC

Lung Cancer 2016
31780656 The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

de Los Fayos Alonso, IG, Probst, NA, Prokoph, N, Tangermann, S, Martinez, S, Pastor, J, Turner, SD, Manners, E, Luo, J, Matthews, JD, Kenner, L, Kodajova, P, Merkel, O, Reynolds, CP, Amos Burke, GA, Han, M, Blanco-Aparicio, C, Jahangiri, L, Högler, S, Lim, HK, Lee, LC, Trigg, RM

Nat Commun 2019
29455642 Role and targeting of anaplastic lymphoma kinase in cancer

Troiani, T, Viscardi, G, Morgillo, F, Fasano, M, Martinelli, E, Ciardiello, F, Della Corte, CM, Di Liello, R

Mol. Cancer 2018
25421750 Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma

Piazza, R, Ceccon, M, Giudici, G, Mologni, L, Fontana, D, Gambacorti-Passerini, C, Pirola, A

Mol. Cancer Res. 2015
27780853 The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

Mohemmad, Q, Keats, J, Dalgarno, D, Jang, HG, Anjum, R, Wang, Y, Zou, D, Nadworny, S, Huang, WS, Miller, D, Moran, L, Eichinger, L, Miret, J, Zhang, S, Shakespeare, WC, Ning, Y, Liu, S, Squillace, R, Ye, E, Rivera, VM, Clackson, T, Wardwell, SD, Wang, F, Narasimhan, N, Zhou, T, Song, Y, Zhu, X

Clin. Cancer Res. 2016
21154129 Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases

Shapiro, GI, Rodig, SJ

Curr Opin Investig Drugs 2010
28122866 Targeting ALK: Precision Medicine Takes on Drug Resistance

Shaw, AT, Riely, GJ, Lin, JJ

Cancer Discov 2017
24670165 Ceritinib in ALK-rearranged non-small-cell lung cancer

Thomas, M, Solomon, BJ, Boral, AL, Shaw, AT, Liu, G, Kim, DW, Tan, DS, Chow, LQ, Sharma, S, Engelman, JA, Schuler, M, Mehra, R, Felip, E, Lau, YY, Vansteenkiste, J, Goldwasser, M, Wolf, J, De Pas, T, Santoro, A, Riely, GJ, Camidge, DR

N. Engl. J. Med. 2014
26708155 Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial

Gold, KA, Socinski, MA, Chao, BH, Borghaei, H, Henschel, V, Gandhi, L, Ou, SI, Shaw, AT, Balas, B, Puig, O, Chiappori, A, Zeaiter, A, Gadgeel, S, Bordogna, W, Riely, GJ, Mekhail, T, Cetnar, J, West, H, Camidge, DR

Lancet Oncol. 2016
31585938 Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer

Friboulet, L, Solary, E, Deas, O, Thiery, JP, Bahleda, R, Naltet, C, Tesson, P, Samofalova, D, Richon, C, Braye, F, Facchinetti, F, Galissant, J, Mahjoubi, L, Gazzah, A, Angevin, E, Nicotra, C, Scoazec, JY, Hollebecque, A, Olaussen, KA, Lavaud, P, Soria, JC, Planchard, D, Bigot, L, Andre, F, Tselikas, L, Frias, RL, Recondo, G, Eggermont, AM, Sourisseau, T, Ngo-Camus, M, Besse, B, Michiels, S, Howarth, K, Abou Lovergne, A, Massard, C, De Baere, T, Vassal, G, Lacroix, L, Rizvi, AZ, Mezquita, L, Auger, N

Clin. Cancer Res. 2020
22162641 Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond

Ou, SH

Drug Des Devel Ther 2011
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