ALK mutants bind type I TKIs

Stable Identifier
R-HSA-9700131
Type
Reaction
Species
Homo sapiens
Compartment
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The following ALK mutants and fusion proteins are sensitive to these type I tyrosine kinase inhibitors:
crizotinib:

ALK F1174V: Ceccon et al, 2015
ALK L1198F: Chuang et al, 2019; Ceccon et al, 2015
BCL11A(1-219)InsDHPPA-ALK(1058-1620): Tian et al, 2017
BIRC6(1-958)-ALK(1058-1620): Shan et al, 2015
EIF2AK3(30-144)-ALK(1058-1620): Ali et al, 2016
EML4(1-223)-ALK(1059-1620): Ali et al, 2016
EML4(1-223)insKMSTREKNSQV-ALK(1059-1620): Ali et al, 2016
EML4(1-486)-ALK(1058-1620): Ali et al, 2016; Hrustanovic et al, 2015; Katayama et al, 2011
FN1(32-1201)-ALK(1022-1620): Ren et al, 2012
HIP1(1-1019)-ALK(1058-1620): Ou et al, 2014
HIP1(1-963)-ALK(1058-1620): Hong et al, 2014
HIP1(1-719)InsL-ALK(1059-1620): Fang et al, 2014
PPM1B (1-282)-ALK(1058-1620): Ali et al, 2016
PRKAR1A(1-183)-ALK(1058-1620): Ali et al, 2016
STRN(1-137)-ALK(1058-1620): Kelly et al, 2014


NVP-TAE684:

ALK F1174L: George et al, 2008; Heuckmann et al, 2011
ALK V1180L: Katayama et al, 2014
ALK L1196M: Heuckmann et al, 2011
ALK L1196Q: Ceccon et al, 2013
ALK G1269S: Heuckmann, 2011
ALK R1275Q: George, 2008
CLTC(2-1634)-ALK(1059-1620): Cerchietti et al, 2011
EML4(1-223)insKMSTREKNSQV -ALK(1059-1620): Heuckmann, 2011
FN1(32-1201)-ALK(1022-1620): Ren et al, 2012
NPM1(1-117)-ALK(1058-1620): Galkin et al, 2007
STRN(1-137)-ALK(1058-1620): Kelly et al, 2014

ceritinib:

ALK I1171T: Friboulet et al, 2014; Katayama et al, 2014
ALK F1174V: Ceccon et al, 2015
ALK V1180L: Katayama et al, 2014
ALK S1206Y: Friboulet et al, 2014;
ALK G1269A: Friboulet et al, 2014;
EML4(1-486)-ALK(1058-1620): Hrustanovic et al, 2015

brigatinib:

ALK F1174V: Ceccon et al, 2015
ALK V1180L: Katayama et al, 2014
ALK L1196Q: Ceccon et al, 2013
NPM1(1-117)-ALK(1058-1620): Ceccon et al, 2015


alectinib:

ALK F1174I: Ou et al, 2016
ALK F1174L: Ou et al, 2016
ALK F1174V: Ou et al, 2016; Ceccon et al, 2015 (moderate)
EML4(1-223)-ALK(1059-1620): Ou et al, 2014
EML4(1-223)insKMSTREKNSQV-ALK(1059-1620): Ou et al, 2014
EML4(1-486)-ALK(1058-1620): Davare et al, 2015
HIP1(1-1019)-ALK(1058-1620):Ou et al, 2014

ASP3026:

ALK V1180L: Katayama et al, 2014

Entrectinib:

ALK C1156Y: Ardini et al, 2016
ALK L1196M: Ardini et al, 2016
EML4(1-223)-ALK(1059-1620): Ardini et al, 2016
EML4(1-223)insKMSTREKNSQV-ALK(1059-1620): Ardini et al, 2016
EML4(1-486)-ALK(1058-1620): Ardini et al, 2016
NPM1(1-117)-ALK(1058-1620): Ardini et al, 2016

Literature References
PubMed ID Title Journal Year
24613930 Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer

Altschuler, DL, Nikiforov, YE, Ferris, RL, Hodak, SP, Liu, P, Kelly, LM, Nikiforova, MN, Yu, YP, Dacic, S, Trivedi, S, Luo, J, Barila, G, Panebianco, F, Gandhi, M, Carty, SE, Evdokimova, VN

Proc Natl Acad Sci U S A 2014
21494621 Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas

Reiter, A, Siebert, R, Melnick, A, Pott, C, Damm-Welk, C, Yang, SN, Klapper, W, Harder, L, Vater, I, Woessmann, W, Cerchietti, L

PLoS One 2011
21948233 ALK mutations conferring differential resistance to structurally diverse ALK inhibitors

Lovly, CM, Grütter, C, Heynck, S, Sos, ML, Thomas, RK, Peifer, M, Balke-Want, H, Heuckmann, JM, Rauh, D, Koker, M, Weiss, J, Pao, W, Hölzel, M

Clin. Cancer Res. 2011
28404650 Identification of a novel crizotinib-sensitive BCL11A-ALK gene fusion in a nonsmall cell lung cancer patient

Li, ZW, Deng, WJ, Tian, Q

Eur Respir J 2017
22570254 Identification of anaplastic lymphoma kinase as a potential therapeutic target in ovarian cancer

Haack, H, Ren, JM, Gu, TL, Zhu, X, Innocenti, G, Crosby, K, Tan, ZP, Moritz, A, Yang, YF, Ren, H, Rush, J, Beausoleil, S, Comb, MJ, Zhang, Y, Zhou, XM

Cancer Res 2012
26301689 RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer

Okimoto, RA, Rosell, R, Aisner, DL, Collisson, EA, Doebele, RC, Vaishnavi, A, Riess, JW, Lovly, CM, Blakely, CM, Olivas, V, Ou, SH, Sabnis, A, Bivona, TG, Karachaliou, N, Tulpule, A, Lin, L, Hrustanovic, G, Flanagan, J, Mack, PC, Ichihara, E, Chan, E, Asthana, S, Varella-Garcia, M, Neel, DS, Pazarentzos, E

Nat Med 2015
24496003 HIP1-ALK, a novel ALK fusion variant that responds to crizotinib

Wang, Z, Christensen, J, Zhang, C, Mao, M, Li, J, Sun, H, Ozeck, M, Fang, DD, Chan, CC, Chen, X, Gu, Q, Sheng, W, Chen, KX, Qian, M, Zhang, B, Xu, Q, Lira, M, Chen, SH

J Thorac Oncol 2014
27245569 Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization

Ganesan, S, Hensing, T, Nowak, J, Ou, SH, Allen, J, Ross, JS, Wakelee, H, Schrock, AB, He, J, Zakowski, M, Frampton, GM, Gowen, K, Miller, VA, Menon, S, Chmielecki, J, Ladanyi, M, Molina, JR, Zauderer, M, Klempner, SJ, Peled, N, Firozvi, K, Ali, SM, Stephens, PJ, Fischbach, N, MacMahon, H, Lipson, D, Suh, JH, Sanford, E, Salgia, R, Elvin, JA, Chalmers, Z, Brahmer, JR, Yelensky, R, Kulkarni, A

Oncologist 2016
26939704 Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Pesenti, E, De Ponti, C, Ballinari, D, Amboldi, N, Texido, G, Anderson, D, Saccardo, MB, Harris, J, Orsini, P, Pulci, R, Banfi, P, Felder, E, Ciomei, M, Donati, D, Li, G, Wei, G, Menichincheri, M, Isacchi, A, Bosotti, R, Bandiera, T, Avanzi, N, Ardini, E, Vernier, JM, Mologni, L, Magnaghi, P, Degrassi, A, Galvani, A, Casero, D

Mol Cancer Ther 2016
25393796 Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib

Azada, M, Klempner, SJ, Schrock, AB, Ali, SM, Ou, SH, Stephens, PJ, Miller, VA, Ross, JS, Greenbowe, JR

J Thorac Oncol 2014
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
25228534 Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib

Okuno, Y, Iafrate, AJ, Friboulet, L, Koike, S, Shaw, AT, Engelman, JA, Khan, TM, Lockerman, EL, Takeuchi, K, Taiji, M, Fujita, N, Gainor, JF, Katayama, R

Clin Cancer Res 2014
24675041 The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer

Sun, F, Crystal, AS, Awad, MM, Li, N, Friboulet, L, Michellys, PY, Kasibhatla, S, Lee, CC, Shaw, AT, Li, J, Harris, JL, Engelman, JA, Kim, S, Lockerman, EL, Yanagitani, N, Mahmood, S, Nishio, M, McNamara, P, Pferdekamper, AC, Hua, S, Fujita, N, Gainor, JF, Sun, X, Katayama, R

Cancer Discov 2014
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
18923525 Activating mutations in ALK provide a therapeutic target in neuroblastoma

Zozulya, S, George, RE, Gilliland, DG, Morris, SW, Luther, W, London, WB, Hanna, M, Meyerson, M, McGrady, P, Sanda, T, Gregor, VE, Look, AT, Zhang, J, Fröhling, S, Ahn, Y, Diller, L, Webb, TR, Zhou, W, Greulich, H, Gray, NS, Xue, L

Nature 2008
26001147 BIRC6-ALK, a Novel Fusion Gene in ALK Break-Apart FISH-Negative Lung Adenocarcinoma, Responds to Crizotinib

Ying, J, Zeng, Y, Wu, J, Xu, F, Zhang, W, Jiao, Y, Jiang, P, Guo, L, Shan, L

J Thorac Oncol 2015
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
24518094 HIP1-ALK, a novel fusion protein identified in lung adenocarcinoma

Kim, RN, Choi, YL, Song, JY, Han, J, Takeuchi, K, Mao, M, Kim, J, Oh, E, Lira, ME, Choi, SJ, Hong, M

J Thorac Oncol 2014
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
31388026 Molecular Modeling of ALK L1198F and/or G1202R Mutations to Determine Differential Crizotinib Sensitivity

Chang, HW, Yang, CN, Chuang, YC, Huang, BY

Sci Rep 2019
21502504 Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

Khan, TM, Iafrate, AJ, Shakespeare, WC, Shaw, AT, Lifshits, E, Rivera, VM, Ebi, H, Engelman, JA, Benes, C, Katayama, R

Proc. Natl. Acad. Sci. U.S.A. 2011
Participants
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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