Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma

Makoto Nakagawa, Fumihiko Nakatani, Hironori Matsunaga, Takahiko Seki, Makoto Endo, Yoko Ogawara, Yukino Machida, Takuo Katsumoto, Kazutsune Yamagata, Ayuna Hattori, Shuhei Fujita, Yukiko Aikawa, Takamasa Ishikawa, Tomoyoshi Soga, Akira Kawai, Hirokazu Chuman, Nobuhiko Yokoyama, Suguru Fukushima, Kenichiro Yahiro, Atsushi KimuraEijiro Shimada, Takeshi Hirose, Toshifumi Fujiwara, Nokitaka Setsu, Yoshihiro Matsumoto, Yukihide Iwamoto, Yasuharu Nakashima, Issay Kitabayashi

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

Original languageEnglish
Pages (from-to)6835-6849
Number of pages15
JournalOncogene
Volume38
Issue number42
DOIs
Publication statusPublished - 2019 Oct 17

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Nakagawa, M., Nakatani, F., Matsunaga, H., Seki, T., Endo, M., Ogawara, Y., Machida, Y., Katsumoto, T., Yamagata, K., Hattori, A., Fujita, S., Aikawa, Y., Ishikawa, T., Soga, T., Kawai, A., Chuman, H., Yokoyama, N., Fukushima, S., Yahiro, K., ... Kitabayashi, I. (2019). Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma. Oncogene, 38(42), 6835-6849. https://doi.org/10.1038/s41388-019-0929-9