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LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.

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 EGFR^{L858R/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 EGFR^L858R/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 EGFR^{19del/T790M/C797S} or EGFR^{L858R/T790M/C797S} , and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR^{19del/T790M/C797S} (named PC-9-OR cells) using the CRISPR/Cas9 system and found that LS-106 markedly suppressed the activation of EGFR^{19del/T790M/C797S} and the proliferation of PC-9-OR cells. Moreover, cells harboring EGFR^{19del/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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8819286 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.

Liu Yingqiang Y Lai Mengzhen M Li Shan S Wang Yanan Y Feng Fang F Zhang Tao T Tong Linjiang L Zhang Mengge M Chen Hao H Chen Yi Y Song Peiran P Li Yan Y Bai Gang G Ning Yi Y Tang Haotian H Fang Yan Y Chen Yi Y Lu Xiaoyun X Geng Meiyu M Ding Ke K Yu Ker K Xie Hua H Ding Jian J

Cancer science 20211216 2

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 act ...[more]

PMID: 34855271

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LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.

Publications

LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.

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