首页> 外文期刊>International Journal of Cancer =: Journal International du Cancer >Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models
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Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models

机译:HM781-36B(一种有效的泛HER抑制剂)在耐厄洛替尼的NSCLC和其他EGFR依赖性癌症模型中的抗肿瘤活性

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摘要

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781-36B. The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746-A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781-36B is the most potent pan-HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.
机译:受体酪氨酸激酶的表皮生长因子受体(EGFR)家族与多种癌症有关。特别是,EGFR酪氨酸激酶结构域的第21外显子的L858R点突变和第19外显子的框内缺失等活化突变与非小细胞肺癌(NSCLC)患者对EGFR酪氨酸激酶抑制剂的敏感性相关。患者的临床治疗受到主要由网守突变(T790M)引起的耐药性发展的限制。在这项研究中,我们评估了新型不可逆的pan-HER抑制剂HM781-36B的治疗潜力。这项研究的结果表明,与其他EGFR酪氨酸激酶抑制剂(厄洛替尼)相比,HM781-36B是一种有效的EGFR体外抑制剂,包括EGFR获得性抗性突变(T790M)以及HER-2和HER-4 ,拉帕替尼和BIBW2992)。 HM781-36B处理带有EGFR DelE746-A750的厄洛替尼敏感性HCC827和带有EGFR L858R / T790M带有埃洛替尼的耐NCI-H1975 NSCLC细胞的治疗会抑制EGFR磷酸化并随后使下游信号蛋白失活。此外,HM781-36B在多种依赖EGFR和HER-2的肿瘤异种移植模型中显示出优异的疗效,包括埃洛替尼敏感性HCC827 NSCLC细胞,耐埃洛替尼的NCI-H1975 NSCLC细胞,HER-2过表达Calu-3 NSCLC细胞,NCI-N87胃癌细胞,SK-Ov3卵巢癌细胞和EGFR过表达的A431表皮样癌细胞。根据这些临床前结果,HM781-36B是最有效的pan-HER抑制剂,对于治疗NSCLC患者(包括因获得性突变引起的临床缺陷(EGFR T790M),乳腺癌和胃癌)具有优势。

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