2. Academic Validation
  3. The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas

The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas

  • Cell Death Discov. 2018 May 10;4:56. doi: 10.1038/s41420-018-0059-0.
Makoto Miyazaki 1 2 3 4,  Ryo Otomo 1 5,  Yuko Matsushima-Hibiya 1 4,  Hidenobu Suzuki 1 4 6,  Ayana Nakajima 1 4 7,  Naomi Abe 1 4,  Arata Tomiyama 1 4 8,  Koichi Ichimura 4,  Koichi Matsuda 2,  Toshiki Watanabe 3,  Takahiro Ochiya 9,  Hitoshi Nakagama 10,  Ryuichi Sakai 1 11,  Masato Enari 1
Affiliations

Affiliations

  • 1 1Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045 Japan.
  • 2 2Department of Computational Biology and Medical Sciences, Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo 108-8639 Japan.
  • 3 3Department of Computational Biology and Medical Sciences, Tumour Cell Biology, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo 108-8639 Japan.
  • 4 4Division of Brain Tumour Translational Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045 Japan.
  • 5 11Present Address: Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694 Japan.
  • 6 5Department of NCC Cancer Science, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 Japan.
  • 7 6Molecular and Cellular Biology Laboratory, Graduate school of Medical Life Science, Yokohama City University, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan.
  • 8 7Department of Neurosurgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513 Japan.
  • 9 8Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045 Japan.
  • 10 9Division of Cancer Development System, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045 Japan.
  • 11 10Division of Biochemistry, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan.
PMID: 29760954 DOI: 10.1038/s41420-018-0059-0
Abstract

Anaplastic lymphoma kinase (ALK) is an oncogenic receptor tyrosine kinase that is activated by gene amplification and mutation in neuroblastomas. ALK inhibitors can delay the progression of ALK-driven cancers, but are of limited use owing to ALK inhibitor resistance. Here, we show that resistance to ALK inhibitor in ALK-driven neuroblastomas can be attenuated by combination treatment with a p53 activator. Either ALK inhibition or p53 activator treatment induced cell cycle arrest, whereas combination treatment induced Apoptosis, and prevented tumour relapse both in vitro and in vivo. This shift toward Apoptosis, and away from cell-cycle arrest, in the presence of an ALK inhibitor and a p53 activator, is mediated by inhibition of the ALK-AKT-FOXO3a axis leading to a specific upregulation of SOX4. SOX4 cooperates with p53 to upregulate the pro-apoptotic protein PUMA. These data therefore suggest a novel combination therapy strategy for treating ALK-driven neuroblastomas.

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