Biomaterial Database

Potent antitumor activity of ensartinib in MET exon 14 skipping-mutated non-small cell lung cancer. 2023

Yang Xia, and Rui Jin, and Miao Li, and Fen Lan, and Hao Zhu, and Yinghui Yu, and Da Miao, and Qiyuan Wang, and Yi Zhou, and Giovanni Selvaggi, and Songmin Ying, and Jianjun Zhang, and Huahao Shen, and Xiuning Le, and Wen Li

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of ensartinib were 67% and 94% in cohort 1, and 73% and 91% in cohort 2. The median DoR was 6.8 months and median PFS was 6.1 months in the total population. Rash was the most common drug-related adverse event, and peripheral edema of any grade was reported in only 9% patients. Molecular simulations indicated favorable binding of ensartinib to c-MET. The kinase assay demonstrated an IC50 of 7.9 nM of ensartinib against METex14 protein. In vitro, Hs746T (METex14 mutation) and EBC-1 (MET amplification) cells were sensitive to ensartinib, with IC50 values of 31 and 44 nM, respectively. Ensartinib exhibited comparable inhibitory effects on cell migration as crizotinib and tepotinib in both cell types. In vivo, ensartinib suppressed the growth of Hs746T cells. Ensartinib also potently inhibited the viability of PDOs. Overall, Ensartinib exhibited substantial antitumor effects against METex14 mutant NSCLCs in preclinical and clinical trials, with relatively low peripheral edema rates.

UI	MeSH Term	Description	Entries
D008175	Lung Neoplasms	Tumors or cancer of the LUNG.	Cancer of Lung,Lung Cancer,Pulmonary Cancer,Pulmonary Neoplasms,Cancer of the Lung,Neoplasms, Lung,Neoplasms, Pulmonary,Cancer, Lung,Cancer, Pulmonary,Cancers, Lung,Cancers, Pulmonary,Lung Cancers,Lung Neoplasm,Neoplasm, Lung,Neoplasm, Pulmonary,Pulmonary Cancers,Pulmonary Neoplasm
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D002289	Carcinoma, Non-Small-Cell Lung	A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy.	Carcinoma, Non-Small Cell Lung,Non-Small Cell Lung Cancer,Non-Small Cell Lung Carcinoma,Non-Small-Cell Lung Carcinoma,Nonsmall Cell Lung Cancer,Carcinoma, Non Small Cell Lung,Carcinomas, Non-Small-Cell Lung,Lung Carcinoma, Non-Small-Cell,Lung Carcinomas, Non-Small-Cell,Non Small Cell Lung Carcinoma,Non-Small-Cell Lung Carcinomas
D005091	Exons	The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.	Mini-Exon,Exon,Mini Exon,Mini-Exons
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077547	Crizotinib	A piperidine and aminopyridine derivative that acts as an inhibitor of RECEPTOR PROTEIN-TYROSINE KINASES, including ANAPLASTIC LYMPHOMA KINASE (ALK) and HEPATOCYTE GROWTH FACTOR RECEPTOR (HGFR; c-Met). It is used in the treatment of NON-SMALL CELL LUNG CANCER.	PF 02341066,PF-02341066,PF-2341066,PF02341066,Xalkori,PF 2341066,PF2341066
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D047428	Protein Kinase Inhibitors	Agents that inhibit PROTEIN KINASES.	Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D019859	Proto-Oncogene Proteins c-met	Cell surface protein-tyrosine kinase receptors for HEPATOCYTE GROWTH FACTOR. They consist of an extracellular alpha chain which is disulfide-linked to the transmembrane beta chain. The cytoplasmic portion contains the catalytic domain and sites critical for the regulation of kinase activity. Mutations in the c-met proto-oncogene are associated with papillary renal carcinoma and other neoplasia.	HGF Receptor,Hepatocyte Growth Factor Receptor,c-met Proteins,met Proto-Oncogene Proteins,MET Proto-Oncogene, Receptor Tyrosine Kinase,MET Receptor Tyrosine Kinase,Receptor, HGF,Receptor, Hepatocyte Growth Factor,Receptor, Scatter Factor,Scatter Factor Receptor,c-Met Receptor Tyrosine Kinase,MET Proto Oncogene, Receptor Tyrosine Kinase,Proto Oncogene Proteins c met,Proto-Oncogene Proteins, met,c Met Receptor Tyrosine Kinase,c met Proteins,met Proto Oncogene Proteins