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.
Highlights
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in neuronal cells at an early stage of human development; it is assumed that ALK contributes to neural tissue development [1, 2]
We adopted comprehensive in vitro and in vivo experimental approaches that allowed in depth characterization of the effects of the recently www.impactjournals.com/oncotarget developed ALK inhibitor ASP3026 in NPM-ALK+ anaplastic large-cell lymphoma (ALCL)
Our in vitro experiments demonstrated that ASP3026 causes a marked decrease in the viability of NPM-ALK+ ALCL cells, which could be at least partially explained by a significant increase in apoptotic cell death
Summary
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in neuronal cells at an early stage of human development; it is assumed that ALK contributes to neural tissue development [1, 2]. The expression of ALK in this lymphoma occurs secondary to one of several chromosomal aberrations that involve the ALK gene on chromosome 2p23. (p23;q35) that occurs in 85% of ALK+ ALCL cases [3, 4]. This translocation involves the nucleophosmin (NPM) gene and induces the generation of the oncogenic tyrosine kinase NPM-ALK. Wild-type NPM is involved in the formation of NPM/ NPM-ALK heterodimers that translocate to the nucleus [5]. Because NPM-ALK is the most widely expressed ALK chimeric protein and because all established ALK+
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