title: The ALK inhibitor ASP3026 eradicates NPM-ALK⁺ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model.
abstract: NPM-ALK⁺ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK⁺ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK⁺ solid tumors. However, NPM-ALK⁺ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK⁺ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK⁺ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK⁺ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK⁺ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; These authors contributed equally to this work.
authors.forename: Suraj Konnath
authors.initials: SK
authors.lastname: George
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; The University of Texas Graduate School of Biomedical Sciences, Houston, TX; These authors contributed equally to this work.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Vishwamitra
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; The University of Texas Graduate School of Biomedical Sciences, Houston, TX.
authors.forename: Roxsan
authors.initials: R
authors.lastname: Manshouri
authors.affiliation: State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; The University of Texas Graduate School of Biomedical Sciences, Houston, TX.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595153:ASP3026; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D014227:Triazines