Abstract
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase expressed at early stages of normal development and in various cancers including ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), in which it is the main therapeutic target. ALK tyrosine kinase inhibitors (ALK TKIs) have greatly improved the prognosis of ALK+ALCL patients, but the emergence of drug resistance is inevitable and limits the applicability of these drugs. Although various mechanisms of resistance have been elucidated, the problem persists and there have been relatively few relevant clinical studies. This review describes research progress on ALK+ ALCL including the application and development of new therapies, especially in relation to drug resistance. We also propose potential treatment strategies based on current knowledge to inform the design of future clinical trials.
Highlights
Anaplastic large cell lymphoma (ALCL) is an aggressive cluster of differentiation (CD)30+ peripheral T-cell lymphoma (PTCL) that accounts for approximately 10%–15% of pediatric and 1%–2% of adult non-Hodgkin lymphoma (NHL) cases [1]
Alectinib was approved in Japan for the treatment of children and adults with relapsed/refractory (R/R) NPM–Anaplastic lymphoma kinase (ALK)+ ALCL, while crizotinib has been approved for this indication by the US Food and Drug Administration
It was recently reported that NPM–ALK mediates STAT3 acetylation to inhibit the expression of tumor suppressor genes; inhibiting STAT3 acetylation resulted in their re-expression and ALCL cell apoptosis [33] (Figure 1)
Summary
Anaplastic large cell lymphoma (ALCL) is an aggressive cluster of differentiation (CD)30+ peripheral T-cell lymphoma (PTCL) that accounts for approximately 10%–15% of pediatric and 1%–2% of adult non-Hodgkin lymphoma (NHL) cases [1]. Over 90% of children and adolescents with ALCL are ALK positive (ALK+) while the rate among adult patients is 40%–50% [2]. NPM–ALK is the most prevalent of these fusions and is detected in 75%–80% of adults and 90% of children with ALK+ ALCL [7, 8]. In ALK+ ALCL, NPM–ALK is highly expressed as a result of a high copy number of the NPM promoter and constitutively activates NPM–ALK and downstream signaling including signal transducer and activator of transcription (STAT), phospholipase (PLC)g, phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT), and mitogen-activated protein kinase (MAPK)– extracellular signal-regulated kinase (ERK) pathways that are important for cell survival and. Alectinib was approved in Japan for the treatment of children and adults with relapsed/refractory (R/R) NPM–ALK+ ALCL, while crizotinib has been approved for this indication by the US Food and Drug Administration. Tumors survive by other mechanisms such as autophagy, anti-apoptosis, and ALK bypass substitution, among others
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