Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance
Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance
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发现新型第三代 EGFR 抑制剂并确定克服耐药性的潜在组合策略
DOI：
10.1186/s12943-020-01202-9
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发表时间：
2020-05-13
期刊：
影响因子：
37.3
通讯作者：
Xie, Hua
中科院分区：
文献类型：
--
作者：
Zhang, Tao;Qu, Rong;Xie, Hua
背景EGFR突变激活的非小细胞肺癌（NSCLC）患者最初对第一代EGFR抑制剂有反应;然而，这些药物的疗效受到EGFRT 790 M突变驱动的获得性耐药的限制。第三代EGFR抑制剂克服EGFRT 790 M的发现及其新的耐药机制引起了人们的广泛关注。MethodsWe研究了一种新的EGFR第三代抑制剂在体外和体内的抗肿瘤活性和潜在的耐药机制，采用ELISA，SRB测定，免疫印迹，流式细胞仪分析，激酶阵列，qRT-PCR和肿瘤异种移植模型。对病人的临床效果进行了评估，通过计算机断层扫描。ResultsWe确定化合物ASK 120067作为一种新的抑制剂EGFRT 790 M，选择性超过EGFRWT。ASK 120067在携带EGFRT 790 M（NCI-H1975）和致敏突变（PC-9和HCC 827）的肿瘤细胞中显示出强效抗增殖活性，而在表达EGFRWT的细胞中显示出中度或弱抑制作用。在NSCLC异种移植模型和携带EGFRT 790 M的PDX模型中，经口给予ASK 120067可诱导肿瘤消退。1例晚期EGFR T790 M阳性NSCLC患者的治疗被描述为原则证明。此外，我们发现Ack 1的过度磷酸化和随后通过AKT途径激活抗凋亡信号有助于ASK 120067抗性。伴随着EGFR和Ack 1的靶向有效地推翻了获得性耐药的ASK 120067在体外和在vivo.ConclusionsOur结果证明ASK 120067作为一个有前途的第三代EGFR抑制剂，并首次揭示，Ack 1激活作为一种新的耐药机制，EGFR抑制剂，指导潜在的组合策略。
BackgroundNon-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFRT790Mmutation. The discovery of third-generation EGFR inhibitors overcoming EGFRT790Mand their new resistance mechanisms have attracted much attention.MethodsWe examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan.ResultsWe identified compound ASK120067 as a novel inhibitor of EGFRT790M, with selectivity over EGFRWT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFRT790M(NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFRWT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFRT790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo.ConclusionsOur results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.