The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models

  • Nat Commun. 2019 Aug 9;10(1):3604. doi: 10.1038/s41467-019-11496-z.
Ryohei Katayama  1 ,  Bo Gong  2  3 ,  Noriko Togashi  4 ,  Masaya Miyamoto  4 ,  Masaki Kiga  4 ,  Shiho Iwasaki  4 ,  Yasuki Kamai  4 ,  Yuichi Tominaga  4 ,  Yasuyuki Takeda  4 ,  Yoshiko Kagoshima  4 ,  Yuki Shimizu  2  3 ,  Yosuke Seto  2 ,  Tomoko Oh-Hara  2 ,  Sumie Koike  2 ,  Naoki Nakao  5 ,  Hiroyuki Hanzawa  5 ,  Kengo Watanabe  4 ,  Satoshi Yoda  6  7 ,  Noriko Yanagitani  8 ,  Aaron N Hata  6  7 ,  Alice T Shaw  6  7 ,  Makoto Nishio  8 ,  Naoya Fujita  2  3 ,  Takeshi Isoyama  9
Affiliations
  • 1. Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan. [email protected].
  • 2. Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
  • 3. Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, 108-8639, Japan.
  • 4. Daiichi Sankyo Co., Ltd, Tokyo, 140-8710, Japan.
  • 5. Daiichi Sankyo RD Novare Co., Ltd, Tokyo, 134-8630, Japan.
  • 6. Massachusetts General Hospital Cancer Center, Boston, MA, 02129, USA.
  • 7. Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
  • 8. Department of Thoracic Medical Oncology, the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
  • 9. Daiichi Sankyo Co., Ltd, Tokyo, 140-8710, Japan. [email protected].
PMID: 31399568 DOI: 10.1038/s41467-019-11496-z
Abstract

ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several Other cancers such as cholangiocarcinoma, glioblastoma, or colorectal Cancer. Crizotinib, an ALK/ROS1/Met Inhibitor, is highly effective against ROS1-rearranged lung Cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged Cancer in preclinical models, including crizotinib-resistant ROS1 positive Cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

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