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Potent antitumor activity of ensartinib in MET exon 14 skipping-mutated non-small cell lung cancer.
Xia, Yang; Jin, Rui; Li, Miao; Lan, Fen; Zhu, Hao; Yu, Yinghui; Miao, Da; Wang, Qiyuan; Zhou, Yi; Selvaggi, Giovanni; Ying, Songmin; Zhang, Jianjun; Shen, Huahao; Le, Xiuning; Li, Wen.
Afiliación
  • Xia Y; 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.
  • Jin R; 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.
  • Li M; 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.
  • Lan F; 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.
  • Zhu H; Department of Respiratory and Critical Care Medicine, Wuyi First People's Hospital, Jinhua, Zhejiang, China.
  • Yu Y; 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.
  • Miao D; 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.
  • Wang Q; Department of Radiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • Zhou Y; Xcovery Holdings Inc, Palm Beach Gardens, FL, USA.
  • Selvaggi G; Xcovery Holdings Inc, Palm Beach Gardens, FL, USA.
  • Ying S; 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.
  • Zhang J; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Shen H; 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. Electronic address: huahao
  • Le X; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: xle1@mdanderson.org.
  • Li W; 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. Electronic address: liwen@
Cancer Lett ; 561: 216140, 2023 05 01.
Article en En | MEDLINE | ID: mdl-36948240
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Lett Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Irlanda
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Lett Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Irlanda