Anaplastic lymphoma kinase (ALK) fusion events lead to constitutive activation of the ALK kinase domain, thereby functioning as oncogenic drivers. These fusion proteins have been identified in numerous cancers. Crizotinib, a small molecule inhibitor of c-Met and ALK, is a Food and Drug Administration-approved drug with reported efficacy in the treatment of cancer. Tropomyosins (TPMs) are a family of actin filament-binding proteins. Altered TPM expression has been found in a variety of human tumors. Inhibitors of cancer-associated TPMs and actin-targeting compounds have been developed, but anti-actin agents have cardiac and respiratory muscle toxicities. In this study, we investigated the sensitivities of human TPM4 (hTPM4), human ALK (hALK), and their fusion gene (hTPM4-hALK) to crizotinib by measuring the lifespan of transgenic Drosophila Flies overexpressing hTPM4-hALK, hTPM4 and hALK showed decreased lifespans compared with controls. Although crizotinib is an inhibitor of ALK, treatment with crizotinib significantly extended the lifespans of Drosophila expressing hTPM4 and hTPM4-hALK but had no effect on hALK-expressing flies. Autophosphorylation of Tyr1278 is necessary for full activation of the ALK domain. We confirmed that hTPM4-hALK was phosphorylated at Tyr1278 in a ligand-independent manner, and hTPM4-hALK-expressing flies treated with crizotinib showed a decreased level of Tyr1278 phosphorylation compared with untreated hTPM4-hALK-expressing flies, with a greater decrease induced by 1 µM compared with 200 nM crizotinib. Taken together, the results suggest that crizotinib is effective for treating ALK-driven cancer and might be a new therapeutic drug, without cardiac or respiratory muscle toxic effects, for TPM4-expressing cancers.
Keywords: Cancer; Crizotinib; Drosophila; Fusion gene (TPM4-ALK).
© 2019. Published by The Company of Biologists Ltd.