Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Hayato Mizuta; Koutaroh Okada; Mitsugu Araki; Jun Adachi; Ai Takemoto; Justyna Kutkowska; Kohei Maruyama; Noriko Yanagitani; Tomoko Oh-Hara; Kana Watanabe; Keiichi Tamai; Luc Friboulet; Kazuhiro Katayama; Biao Ma; Yoko Sasakura; Yukari Sagae; Mutsuko Kukimoto-Niino; Mikako Shirouzu; Satoshi Takagi; Siro Simizu; Makoto Nishio; Yasushi Okuno; Naoya Fujita; Ryohei Katayama

doi:10.1038/s41467-021-21396-w

Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Nat Commun. 2021 Feb 24;12(1):1261. doi: 10.1038/s41467-021-21396-w.

Authors

Hayato Mizuta^#^{1

2}, Koutaroh Okada^#^{1

3}, Mitsugu Araki⁴, Jun Adachi⁵, Ai Takemoto¹, Justyna Kutkowska¹, Kohei Maruyama^{1

3}, Noriko Yanagitani⁶, Tomoko Oh-Hara¹, Kana Watanabe⁷, Keiichi Tamai⁸, Luc Friboulet⁹, Kazuhiro Katayama¹⁰, Biao Ma¹¹, Yoko Sasakura¹¹, Yukari Sagae⁴, Mutsuko Kukimoto-Niino¹², Mikako Shirouzu¹², Satoshi Takagi¹, Siro Simizu², Makoto Nishio⁶, Yasushi Okuno⁴, Naoya Fujita¹, Ryohei Katayama^{13

14}

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. ryohei.katayama@jfcr.or.jp.
¹⁴ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. ryohei.katayama@jfcr.or.jp.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines
Aniline Compounds / therapeutic use*
Animals
Apoptosis / physiology
Benzamides / therapeutic use
Carbazoles / therapeutic use
Cell Line
Cell Survival / physiology
Crizotinib / therapeutic use
Drug Resistance, Neoplasm / genetics
Enzyme Inhibitors / therapeutic use*
Humans
Immunoblotting
Indazoles / therapeutic use
Lactams
Lactams, Macrocyclic / therapeutic use*
Lung Neoplasms / drug therapy
Lung Neoplasms / enzymology
Mice
Mice, Inbred BALB C
Molecular Dynamics Simulation
Neoplasm Recurrence, Local
Piperidines / therapeutic use
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Pyrazines / therapeutic use*
Pyrazoles
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism

Substances

Aminopyridines
Aniline Compounds
Benzamides
Carbazoles
Enzyme Inhibitors
Indazoles
Lactams
Lactams, Macrocyclic
Piperidines
Proto-Oncogene Proteins
Pyrazines
Pyrazoles
gilteritinib
Crizotinib
Receptor Protein-Tyrosine Kinases
Ros1 protein, mouse
entrectinib
alectinib
lorlatinib