2. Academic Validation
  3. Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

  • Nat Commun. 2021 Feb 24;12(1):1261. doi: 10.1038/s41467-021-21396-w.
Hayato Mizuta  # 1 2,  Koutaroh Okada  # 1 3,  Mitsugu Araki 4,  Jun Adachi 5,  Ai Takemoto 1,  Justyna Kutkowska 1,  Kohei Maruyama 1 3,  Noriko Yanagitani 6,  Tomoko Oh-Hara 1,  Kana Watanabe 7,  Keiichi Tamai 8,  Luc Friboulet 9,  Kazuhiro Katayama 10,  Biao Ma 11,  Yoko Sasakura 11,  Yukari Sagae 4,  Mutsuko Kukimoto-Niino 12,  Mikako Shirouzu 12,  Satoshi Takagi 1,  Siro Simizu 2,  Makoto Nishio 6,  Yasushi Okuno 4,  Naoya Fujita 1,  Ryohei Katayama 13 14
Affiliations

Affiliations

  • 1 Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 2 Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Kanagawa, Japan.
  • 3 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
  • 4 Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 5 Laboratory of Proteomics for Drug Discovery, Laboratory of Clinical and Analytical Chemistry, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
  • 6 Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 7 Department of Respiratory Medicine, Miyagi Cancer Center, Miyagi, Japan.
  • 8 Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Miyagi, Japan.
  • 9 INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France.
  • 10 Laboratory of Molecular Targeted Therapeutics, School of Pharmacy, Nihon University, Chiba, Japan.
  • 11 Research and Development Group for In Silico Drug Discovery, Center for Cluster Development and Coordination (CCD), Foundation for Biomedical Research and Innovation at Kobe (FBRI), Kobe, Japan.
  • 12 RIKEN Center for Biosystems Dynamics Research, Kanagawa, Japan.
  • 13 Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. [email protected].
  • 14 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. [email protected].
  • # Contributed equally.
PMID: 33627640 DOI: 10.1038/s41467-021-21396-w
Abstract

ALK gene rearrangement was observed in 3%-5% of non-small cell lung Cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive Cancer.

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