Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models
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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DOI：
10.1002/ijc.26276
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发表时间：
2012-05-15
影响因子：
6.4
通讯作者：
Kim, Maeng Sup
中科院分区：
文献类型：
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作者：
Cha, Mi Young;Lee, Kwang-Ok;Kim, Maeng Sup
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酪氨酸激酶结构域外显子21中的L 858 R点突变和外显子19中的小框内缺失等激活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看门突变（T790 M）引起的耐药性发展的限制。在这项研究中，我们评估了一种新型的、不可逆的泛HER抑制剂HM 781 - 36 B的治疗潜力。本研究的结果表明，与其他EGFR酪氨酸激酶抑制剂（厄洛替尼、拉帕替尼和BIBW 2992）相比，HM 781 - 36 B是一种有效的体外EGFR抑制剂，包括EGFR获得性耐药突变（T790 M）以及HER-2和HER-4。HM 781 - 36 B处理携带EGFR DelE746_A750的厄洛替尼敏感性HCC 827和携带EGFR L 858 R/T790 M的厄洛替尼耐药NCI-H1975 NSCLC细胞导致EGFR磷酸化抑制和随后下游信号蛋白失活。此外，HM 781 - 36 B在多种EGFR和HER-2依赖性肿瘤异种移植模型中显示出优异的疗效，包括厄洛替尼敏感性HCC 827 NSCLC细胞、厄洛替尼耐药NCI-H1975 NSCLC细胞、HER-2过表达Calu-3 NSCLC细胞、NCI-N87胃癌细胞、SK-Ov 3卵巢癌细胞和EGFR过表达A431表皮样癌癌细胞。基于这些临床前结果，HM 781 - 36 B是最有效的泛HER抑制剂，将有利于治疗NSCLC患者，包括获得性突变（EGFR T790 M）导致的临床限制、乳腺癌和胃癌。
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.