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KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth

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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), non-small 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 NPM-ALK-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.

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Acknowledgements

This work was taken in part from the master’s thesis of J. Hwang and the doctoral thesis of I. Song. We thank the Central Laboratory of Kangwon National University for providing us with technical assistance on the microscopic and cytometry experiments.

Funding

This work was financially supported by National Research Foundation of Korea (NRF) grants (NRF-2012M3A9A9054971 and NRF-2018R1A2B6001314) funded by the Korean government (MSIT).

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Author notes

  1. Jungjoong Hwang and Insuk Song contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon, Gangwon-do, 24341, Republic of Korea

    Jungjoong Hwang, Insuk Song, Eun-Hye Hong, Sung-Hoon Ahn & Jongkook Lee

  2. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea

    Kwangho Lee & Hyoung Rae Kim

  3. Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea

    Jung Soon Hwang

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  1. Jungjoong Hwang
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Correspondence to Jongkook Lee.

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Hwang, J., Song, I., Lee, K. et al. KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth. Invest New Drugs 38, 1282–1291 (2020). https://doi.org/10.1007/s10637-020-00896-4

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