LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.
LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.
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LS-106是一种针对C797S的新型EGFR抑制剂，在体外和体内均表现出抗肿瘤活性
DOI：
10.1111/cas.15229
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发表时间：
2022-03
期刊：
影响因子：
5.7
通讯作者：
Ding J
中科院分区：
文献类型：
--
作者：
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;Ding J
随着第三代表皮生长因子受体（EGFR）抑制剂奥希替尼用于治疗EGFR突变的非小细胞肺癌（NSCLC）的广泛临床应用，EGFR C797S三次突变引起的获得性耐药已成为人们关注的问题。因此，能够克服这种突变的第四代EGFR抑制剂近年来受到越来越多的关注。在这里，我们鉴定了LS‐106作为一种新的抗C797S突变的EGFR抑制剂，并在体外和体内评估了其抗肿瘤活性。在无细胞实验中，LS‐106有效抑制EGFR19del/T790M/C797S和EGFRL858R/T790M/C797S的激酶活性，IC50值分别为2.4 nmol/L和3.1 nmol/L，比奥西替尼更有效。同时，LS‐106对EGFRL858R/T790M和野生型EGFR表现出与奥西替尼相当的激酶抑制作用。细胞实验结果表明，LS‐106在构建的高表达EGFR19del/T790M/C797S或EGFRL858R/T790M/C797S的BaF3细胞中有效阻断EGFR C797S三重突变的磷酸化，从而抑制这些细胞的增殖。我们还利用CRISPR/Cas9系统构建了含有EGFR19del/T790M/C797S的肿瘤细胞（命名为PC‐9‐OR细胞），发现LS‐106显著抑制EGFR19del/T790M/C797S的激活和PC‐9‐OR细胞的增殖。此外，含有EGFR19del/T790M/C797S的细胞在LS‐106处理后发生了显著的凋亡。体内实验进一步证明，口服LS‐106在PC‐9‐OR异种移植模型中引起了显著的肿瘤消退，30和60 mg/kg剂量的肿瘤生长抑制率（TGI）分别为83.5%和136.6%。综上所述，我们确定LS - 106是一种新的第四代抗C797S突变的EGFR抑制剂，并在C797S三突变肿瘤模型中证实了其临床前抗肿瘤作用。在这项研究中，我们发现LS - 106作为一种新的抗EGFR -三突变型表皮生长因子受体（EGFR19del/T790M/C797S和EGFRL858R/T790M/C797S）的抑制剂，在EGFR - C797S -三突变型奥希替尼耐药肿瘤模型中显示出良好的体外和体内抗肿瘤活性。
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 EGFR19del/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. In this study, we identified LS‐106 as a novel inhibitor against C797S–triple‐mutant epidermal growth factor receptor (EGFR) (EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S), which showed great in vitro and in vivo antitumor activity in EGFR‐C797S–triple‐mutant osimertinib‐resistant tumor models.
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