KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth
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PRECLINICAL STUDIES
KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth Jungjoong Hwang 1 & Insuk Song 1 & Kwangho Lee 2 & Hyoung Rae Kim 2 & Eun-Hye Hong 1 & Jung Soon Hwang 3 & Sung-Hoon Ahn 1 & Jongkook Lee 1 Received: 16 December 2019 / Accepted: 10 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Anaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), nonsmall cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPMALK-positive ALCL cells. Additionally, it induced G0/G1 cell cycle arrest and apoptosis by blocking downstream signals including STAT3, Akt, and ERK1/2. Tumor growth was strongly suppressed in mice inoculated with Karpas-299 tumor xenografts and orally treated with KRCA-0008 (50 mg/kg, BID) for 2 weeks. Our results suggest that KRCA-0008 will be useful in further investigations of ALK signaling, and may provide therapeutic opportunities for NPM-ALK-positive ALCL patients. Keywords KRCA-0008 . Anaplastic large cell lymphoma (ALCL) . Anaplastic lymphoma kinase (ALK) inhibitor . Apoptosis . Cell cycle arrest
Introduction Anaplastic lymphoma kinase (ALK) belongs to the insulin receptor tyrosine kinase superfamily. It is mainly expressed in the central and peripheral nervous systems and plays an important role in their development [1, 2]. The normal function of ALK in adult tissue has not yet been completely determined due to its restricted expression. Further, ALK-knockout mice exhibit a normal phenotype and a full lifespan [3]. Jungjoong Hwang and Insuk Song contributed equally to this work. * Jongkook Lee [email protected] 1
College of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon, Gangwon-do 24341, Republic of Korea
2
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
3
Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea
However, this kinase has attracted a great deal of attention because constitutively activated ALK causes a variety of tumor types through chromosomal translocations, point mutations, and gene amplification. Tumor types include anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumor, diffuse large B cell lymphoma, neuroblastoma, and non-small cell lung cancer (NSCLC) [4]. First described by Stein et al. in 1985 [5], ALCL is a subtype of CD30-positive high-grade non-Hodgkin’s lymphoma that usua
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