Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer.

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 1261 (02 24 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33627640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, enzymology)
• Mice
• Mice, Inbred BALB C
• Molecular Dynamics Simulation
• Neoplasm Recurrence, Local
• Piperidines (therapeutic use)
• Proto-Oncogene Proteins (genetics, metabolism)
• Pyrazines (therapeutic use)
• Pyrazoles
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)