ASK120067 (limertinib) exerts pre-clinical anti-tumor activity by inhibiting EGFR exon20 insertion-猫眼课题宝

DOI：

10.3389/fddsv.2022.1050687

发表时间：

2022-11

期刊：

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其他

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作者：

Zhang Tao;Fang Feng;Lin-jiang Tong;Shingpan Chan;Yi Chen;Yan Li;Peiran Song;Yingqiang Liu;Gang Bai;Mengzhen Lai;Yi Ning;Yanan Wang;Yan-feng Fang;Zi-Xiang Pan;M. Geng;K. Ding;Jian Ding;Hua Xie

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）是非小细胞肺癌（NSCLC）个体化治疗的经典策略。然而，EGFR 20号外显子插入（EGFR 20 ins）突变占NSCLC中所有EGFR突变病例的6%-12%，通常对可逆性EGFR TKI（如吉非替尼和厄洛替尼）具有耐药性，这使得它们具有挑战性的肺癌药物靶点。在我们之前的研究中，我们将ASK 120067（limertinib）确定为靶向EGFR T790 M突变的新型第三代EGFR TKI，具有良好的临床活性。在此，我们评估了ASK 120067对EGFR 20 ins活化的效力，并评价了其对EGFR 20 ins驱动的肿瘤模型的体外和体内抗肿瘤活性。我们发现ASK 120067对TKI耐药EGFR 20 ins激酶显示出有效的抑制活性。在TKI耐药EGFR 20 ins依赖性BaF 3细胞中，其剂量依赖性地抑制EGFR磷酸化，阻碍细胞增殖，并诱导细胞凋亡，疗效远上级吉非替尼和厄洛替尼。此外，在EGFR 20 ins BaF 3异种移植模型中，口服ASK 120067可降低磷酸化EGFR 20 ins的水平，并导致显著的肿瘤消退。这些结果显示了ASK 120067在EGFR 20 ins模型中的临床前抗肿瘤疗效，并强调了ASK 120067治疗携带EGFR 20 ins突变的NSCLC患者的潜在价值。

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are classic strategies for the individualized treatment for patients with non-small cell lung cancer (NSCLC). However, EGFR exon20 insertion (EGFR 20ins) mutations, accounting for 6%–12% of all EGFR mutant cases in NSCLC, are generally resistant to the reversible EGFR TKIs (such as gefitinib and erlotinib), which makes them challenging drug-targets in lung cancer. In our previous study, we identified ASK120067 (limertinib) as a novel 3rd-generation EGFR TKI targeting EGFR T790M mutation with promising clinical activities. Here, we accessed the potency of ASK120067 on EGFR 20ins activation and evaluated its in vitro and in vivo anti-tumor activity against EGFR 20ins driven tumor models. We found that ASK120067 showed potent inhibitory activity on TKI-resistant EGFR 20ins kinase. In TKI-resistant EGFR 20ins-dependent BaF3 cells, it dose-dependently suppressed EGFR phosphorylation, impeded cell proliferation, and induced cell apoptosis with much superior efficacy to gefitinib and erlotinib. Moreover, oral administration of ASK120067 decreased the level of phospho-EGFR 20ins and caused significant tumor regression in EGFR 20ins BaF3 xenograft model. These results presented the pre-clinical anti-tumor efficacy of ASK120067 in EGFR 20ins models and highlighted the potential value of ASK120067 for the treatment of NSCLC patients harboring EGFR 20ins mutations.

ASK120067 (limertinib) exerts pre-clinical anti-tumor activity by inhibiting EGFR exon20 insertion

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