Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor

Autor: Masaaki Matsuura, Honami Yonezawa, Naoyuki Nishiya, Tomoko Sakyo, Shingo Dan, Tsutomu Fukuda, Masatomo Iwao, Yusuke Oku, Fumito Ishibashi, Yoko Furukawa, Yuka Sasaki, Takao Yamori, Masaru Ushijima, Yoshimasa Uehara, Tetsuo Mashima, Hiroyuki Seimiya, Akihiro Tomida, Chie Ishikawa, Keishi Otsu, Masanori Abe
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Lung Neoplasms
Fluoroacetates
topoisomerase inhibitor
Gene Expression
Tyrosine-kinase inhibitor
T790M
Mice
0302 clinical medicine
tyrosine kinase inhibitor
Osimertinib
Epidermal growth factor receptor
Molecular Targeted Therapy
Mice
Inbred BALB C
Aniline Compounds
biology
Chemistry
Kinase
Autophosphorylation
General Medicine
ErbB Receptors
Oncology
030220 oncology & carcinogenesis
Heterografts
Original Article
Topoisomerase inhibitor
recurrence
medicine.drug_class
Mice
Nude
Heterocyclic Compounds
4 or More Rings
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Protein Kinase Inhibitors
Cell Proliferation
Acrylamides
Topoisomerase
Original Articles
Molecular biology
lung cancer
030104 developmental biology
Drug Discovery and Delivery
Drug Resistance
Neoplasm
Mollusca
Mutation
biology.protein
Mutagenesis
Site-Directed
Drug Screening Assays
Antitumor
epidermal growth factor receptor
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
Popis: The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third‐generation EGFR‐tyrosine kinase inhibitor (EGFR‐TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR‐TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor‐like biological activity of lamellarin N into kinase inhibitor‐like activity. Ba/F3 and PC‐9 cells expressing the EGFR in‐frame deletion within exon 19 (del ex19)/T790M/C797S triple‐mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple‐mutant EGFR PC‐9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple‐mutant EGFR PC‐9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR‐TKI that prevents the development of cross‐resistance against known drugs in this class.
The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs). One of these EGFR‐TKIs, lamellarin 14, is effective against the C797S mutant EGFR.
Databáze: OpenAIRE
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