BEBT-109, a pan-mutant-selective EGFR inhibitor with potent antitumor activity in EGFR-mutant non-small cell lung cancer
| Autor: | Zhenxian Mo, Weng Yunwo, Lin Mingsheng, Xinjian Liu, Liying Luo, Fan Fushun, Xiaotong Liang, Haiqi Liu, Minhua Zhou, Xiaolan Ye, Cai Xiong, Yaru Ma, Qian Changgeng |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pan-mutant-selective EGFR inhibitor Cancer Research G719S Mutant NSCLC medicine.disease_cause T790M lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine exon20ins In vivo Medicine Osimertinib Lung cancer Original Research EGFR inhibitors Mutation business.industry BEBT-109 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Cancer research business |
| Zdroj: | Translational Oncology, Vol 14, Iss 2, Pp 100961-(2021) Translational Oncology |
| ISSN: | 1936-5233 |
| DOI: | 10.1016/j.tranon.2020.100961 |
| Popis: | Highlights • BEBT-109 is a potent pan-mutant-selective EGFR inhibitor. • Pharmacokinetic profiles of BEBT-109 minimize the off-target toxicity. • Two major metabolites of BEBT-109 show no wild-type EGFR inhibition. • BEBT-109 demonstrates potent antitumor activity in the clinical trial. EGFR mutation-positive NSCLC tumors are highly heterogeneous, therefore, exploring an agent simultaneously targeting multiple EGFR mutations may be valuable for clinical practice. Compared with osimertinib, BEBT-109 shows more sensitive and extensive antitumor activity in EGFR mutant NSCLC, while sparing wild-type EGFR cell lines. Meanwhile, unlike the metabolite of osimertinib AZ5104, the main metabolites of BEBT-109 are found lacking in activity against wild-type EGFR cell lines. Preclinical and clinical studies demonstrate a unique pharmacokinetic profiles of BEBT-109 with rapid absorption and quick in vivo clearance without accumulation, which are conducive to minimizing the off-target toxicity of the covalent irreversible EGFR inhibitor. Oral administration of BEBT-109 induces tumor regression in EGFR exon 20 insertion xenografts, and even tumor disappearance in PC-9, HCC827 and H1975 xenograft models. Furthermore, in clinical trials, the objective responses were observed in NSCLC patients with EGFR T790M mutation in the first and second dosing cohorts. These findings demonstrate that BEBT-109, a potent pan-mutant-selective EGFR inhibitor with improved pharmacokinetic properties, might offer a promising new option for the treatment of multiple mutant-EGFR-driven NSCLC. |
| Databáze: | OpenAIRE |
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