The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor
The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor
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DOI：
10.1158/1535-7163.mct-07-2387
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发表时间：
2008-04-01
影响因子：
5.7
通讯作者：
Haber, Daniel A.
中科院分区：
文献类型：
--
作者：
Godin-Heymann, Nadia;LlIkus, Lindsey;Haber, Daniel A.
在表皮生长因子受体（EGFR）激酶结构域中携带激活突变的非小细胞肺癌（NSCLC）患者往往对酪氨酸激酶抑制剂吉非替尼和厄洛替尼反应良好。然而，在临床反应后，这些患者通常在治疗一年内复发。在许多情况下，耐药是由获得性继发性EGFR激酶结构域突变T790 M引起的。体外研究表明，一类新的EGFR不可逆抑制剂可以克服T790 M赋予的耐药性。目前正在进行临床试验，以检查这些抑制剂之一HKI-272在最初对吉非替尼/厄洛替尼有反应但随后复发的NSCLC患者中的疗效。为了预测对不可逆抑制剂有反应的患者对此类抑制剂产生继发性耐药的可能性，如在其他类似情况下所见，我们在NSCLC细胞培养模型中对EGFR/HER 2双重不可逆酪氨酸激酶抑制剂HKI-272的获得性耐药进行了建模。我们发现，基于药物存在下EGFR磷酸化的保留，HKI-272耐药克隆分为两个生化组。保留磷酸化EGFR的细胞获得了二级突变T790 M。此外，HKI-272仅在超药理学浓度下才能克服T790 M耐药性。我们进一步将EGFR C797突变作为对不可逆EGFR抑制剂耐药的机制进行建模，并表明尽管这些突变体对不可逆抑制剂具有耐药性，但它们保留了厄洛替尼的敏感性。我们的研究结果表明，以最大耐受剂量进行HKI-272治疗可能导致出现T790 M介导的耐药性，而使用更强效的不可逆抑制剂治疗可能在EGFR C797产生耐药性突变。
Patients with non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) kinase domain tend to respond well to the tyrosine kinase inhibitors, gefitinib and erlotinib. However, following clinical response, these patients typically relapse within a year of treatment. In many cases, resistance is caused by an acquired secondary EGFR kinase domain mutation, T790M. In vitro studies have shown that a new class of EGFR-irreversible inhibitors could overcome the resistance conferred by T790M. Clinical trials are under way to examine the efficacy of one of these inhibitors, HKI-272, in patients with NSCLC who initially responded to gefitinib/erlotinib and subsequently relapsed. To anticipate the possibility that patients who respond to irreversible inhibitors will develop secondary resistance to such inhibitors, as has been seen in other similar settings, we modeled acquired resistance to the dual EGFR/HER2-irreversible tyrosine kinase inhibitor HKI-272 in a NSCLC cell culture model. We found that HKI-272-resistant clones fall into two biochemical groups based on the retention of EGFR phosphorylation in the presence of the drug.. Cells that retain phosphorylated EGFR have acquired the secondary mutation T790M. Moreover, HKI-272 can overcome T790M resistance only at supra-pharmacologic concentrations. We further model mutations at EGFR C797 as a mechanism of resistance to irreversible EGFR inhibitors and show that although these mutants are resistant to the irreversible inhibitor, they retain erlotinib sensitivity. Our findings suggest that HKI-272 treatment at maximally tolerated dosing may lead to the emergence of T790M-mediated resistance, whereas treatment with a more potent irreversible inhibitor could yield a resistance mutation at EGFR C797.