ALK mutants bind TKIs

Stable Identifier
Homo sapiens
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Aberrant signaling by activated forms of ALK can be inhibited by tyrosine kinase inhibitors (TKIs). ALK, like other tyrosine kinase receptors, is activated through a series of phosphorylation and conformational changes that move the receptor from the inactive form to the fully activated form. Type II TKIs bind to the inactive form of the receptor at a site adjacent to the ATP-binding cleft, while type I TKIs bind to the active form (reviewed in Roskoski, 2013). Type I inhibitors crizotinib, brigatinib, alectinib, ceritinib and lorlatinib are all approved for treatment of ALK-dependent cancer. Development of resistance to TKIs is not uncommon, however, either through acquisition of secondary mutations or through activation of bypass pathways that remove the dependence on ALK signaling (reviewed in Lovly and Pao, 2012; Lin et al, 2017; Della Corte et al, 2018).
Literature References
PubMed ID Title Journal Year
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
22323827 Escaping ALK inhibition: mechanisms of and strategies to overcome resistance

Lovly, CM, Pao, W

Sci Transl Med 2012
23201355 Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition

Roskoski, R

Pharmacol. Res. 2013
28122866 Targeting ALK: Precision Medicine Takes on Drug Resistance

Shaw, AT, Riely, GJ, Lin, JJ

Cancer Discov 2017
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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