1. LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.
- Author
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Liu Y, Lai M, Li S, Wang Y, Feng F, Zhang T, Tong L, Zhang M, Chen H, Chen Y, Song P, Li Y, Bai G, Ning Y, Tang H, Fang Y, Chen Y, Lu X, Geng M, Ding K, Yu K, Xie H, and Ding J
- Subjects
- Animals, Humans, Mice, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Molecular Structure, Phosphorylation drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Mutation drug effects, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use
- Abstract
With the wide clinical use of the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth-generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS-106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell-free assay, LS-106 potently inhibited the kinase activities of EGFR
19del/T790M/C797S and EGFRL858R/T790M/C797S with IC50 values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS-106 exhibited comparable kinase inhibitory effect to osimertinib on EGFRL858R/T790M and wild-type EGFR. Results from cellular experiments demonstrated that LS-106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR19del/T790M/C797S or EGFRL858R/T790M/C797S , and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR19del/T790M/C797S (named PC-9-OR cells) using the CRISPR/Cas9 system and found that LS-106 markedly suppressed the activation of EGFR19del/T790M/C797S and the proliferation of PC-9-OR cells. Moreover, cells harboring EGFR19del/T790M/C797S underwent remarkable apoptosis upon LS-106 treatment. In vivo experiments further demonstrated that oral administration of LS-106 caused significant tumor regression in a PC-9-OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS-106 as a novel fourth-generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S-triple-mutant tumor models., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)- Published
- 2022
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