痛并快乐着——4年的抗癌路：有限生命的无限选择

慧质兰馨 发表于 2011-10-30 10:06

                               
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7 y: w0 ]' h9 [终于结束二十天的快乐自驾游，往返行程3500公里，真是很开心，身心得到极大的放松，对疾病的认知度 ...

# a5 D5 W) [) H6 H+ p' J8 Q你好幸福啊！有九十六岁的老爸与八十四岁的老妈，而且他们还如此健康。

枫叶红了 发表于 2011-10-30 19:06

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你好幸福啊！有九十六岁的老爸与八十四岁的老妈，而且他们还如此健康。

3 @" s$ F: j7 f7 s" k! f4 q5 n老歌生病第一年，为了不让二老知道病情，不想让他们这么大年纪还为儿女操心，近一年时间没有回家，编排各种理由，一直到吃特罗凯后，病情稳定，才回家。

最爱看你的帖子，你和你家老哥那种快乐的生活状态感人着每一个人。

慧质兰馨 发表于 2011-8-17 21:44

                               
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% V+ d, }* F7 Z* ^讲点伤感的话，前几天老歌化疗后反映很重，半夜因难受睡不着，说不舒服，我知道是化疗反映，但没有办法 ...

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小提琴 发表于 2011-11-1 16:52

                               
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最爱看你的帖子，你和你家老哥那种快乐的生活状态感人着每一个人。

9 d, ?2 s  H0 `" W- A5 q: J+ O; Q高高兴兴是一天，愁眉苦脸还是一天，就看如何选择。生命会随着时间的流失而慢慢远去的，珍惜现在的每一天，过好每一天是最重要的，别给自己吃后悔药。

" F  k2 p& o+ U" Z     朋友将老歌的病历发给美国的二位癌症专家会诊，他们给出如下用药的建议，与各位病友分享，看看对大家有没有帮助。  
9 ^% W+ p* Q- F  d6 v* [  r' ]2 i* x   这个病人不抽烟， 特罗凯使用效果奇好， 就说明他有 EGFR 基因变异。 特罗凯的有效期限是 8 - 12 个月， 他也符合。 我们以前的判断都对。
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现在是是否有办法给病人续命。 下面的内容提到一些还没有成药的抑制剂。主要是 IGF1-R (Insulin like growth factor 1 receptor) 抑制剂。 不知中国能否找到。
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另外， Pan-inhibitors (泛 - 抑制剂 = 多靶位抑制剂）有点用。 目前， 有效的抵抗特罗凯抗药性的方法是同时用两个药， 泛抑制剂加上Erbitux (爱必妥)。

“Resistance to treatmentA key issue with EGFR-directed treatments is that after a period of time, frequently 8–12 months, the cancer cells become resistant to the treatment. The primary source of resistance is a second mutation called T790M. A second source of resistance is the MET mutation.[16]
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( g3 g- u4 I0 s, m" N- TChemically resistance appears to occur by recruiting a mutated IGF-1 receptor to act as one of the EGFR partners in the homodimer, so forming a heterodimer.[17] This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538[18] or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541[19]).
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Pan-inhibitors show some promise in combating resistance, at least in cell studies. Today (3/10) the most promising approach to combating resistance appears to be a dual approach, combining pan-inhibitors like HKI 272 with Erbitux. "Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab (Erbitux) and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance." Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.[20]”
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另一篇 专门讲 怎样战胜特罗凯抗药性的文章。 不知中国能否找到 泛抑制剂HKI-272 和 爱必妥 （后者应当好找）。
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0 j! {4 M; J& x5 S; ^ ADDRESSING TARCEVA RESISTANCE
3 ~+ C2 T! E; |. {* g0 hI. Overview and Background

A. EGFR and lung cancer
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+ U" |0 ~+ C/ XThe human body has a complex system of signaling between cells with gene duplication a normal part of this process.  Duplication is necessary for growth, repair of damaged cells and other functions, and genes signal other cells to initiate replication.  Malfunctions in signaling are a critical part of cancer and the tyrosine kinases have been an important target:
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Uncontrolled proliferation of tumor cells is a hallmark of cancer. In many types of cancer, mutations in genes that activate cellular signal transduction pathways contribute to enhanced proliferation and survival of cancer cells. One well-characterized example is mutation in tyrosine kinases, enzymes that regulate the growth and survival of cells. Tyrosine kinase activity is tightly regulated in normal cells, but is dysregulated due to mutation in some cancers, including lung cancer, resulting in enhanced proliferation and survival of cancer cells. The tyrosine kinases are attractive candidates for molecularly targeted therapy in cancer, because cancers become dependent on growth signals from the mutant tyrosine kinases. Tyrosine kinases require ATP for their enzymic activity, and thus small molecules that mimic ATP can bind to mutant kinases and inactivate them inveas growth factors prompt excessive carcinogenic cell duplication.  Clark (6),
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A subgroup of lung cancer patients has a mutation in the epidermal growth factor receptor (EGFR) which is associated with various forms of cancer, particularly lung. Vikis (2). "Recent work has identified a series of somatic mutations in exons 18 to 21 of epidermal growth factor (EGF) receptor (EGFR) that render lung tumors responsive to the gefitinib and erlotinib therapeutics." Vikis (2). These people are EGFR positive, as measured by a sensitive EGFR mutation test. See Harvard EGFR test.

2 D* l2 W5 X7 M- ]# y) {The response rate to Tarceva for EGFR positive patients is approximately 60%, with response rates further varying upon the particular exon(s) on which the mutation is located.   EGFR positive patients are principally but not exclusively non-smokers with adenocarcinoma.  Some light former smokers and a few squamous cell patients are EGFR positive.  EGFR positive patients appear to have tumors driven by aberrant EGFR signaling. with oncogene addiction, a plausible theory.
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The EGFR is a part of the Erb family of receptors. Cross-signaling among the other receptors including Erb2 occurs, though the precise role of the other receptors in lung cancer is unclear.
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! Y  `7 O+ o  N& @( dWhile the initial response rate to Tarceva is impressive with partial and even complete responses, (total elimination of any visible tumor on Ct to the drug) many patients develop resistance and Tarceva becomes effective. Why do patients develop resistance and what can we do about it are the questions.
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, o* b! J# J3 J. b, iII. The Development of the T790M Mutation

0 y/ }4 D6 R" }A. T790 Mutation
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5 L" e' Z9 R. N0 g3 N6 N# [However, many patients who initially respond to Tarceva find the drug is no longer effective. One cause appears is the development of a Tarceva-resistant EGFR mutation at T790M. "The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme." Vikis (2).  "In patients that progress after drug treatment, it has been observed that a secondary "resistance" mutation is often acquired in exon 20 (4–6). This mutation, T790M, arises somatically in 50% of these cases." Vikis (2).  The change involves threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene." Inukai (3).  "About half of the acquired resistance to EGFR-TKIs that almost always occurs during the course of treatment is caused by a secondary mutation at codon 790 (T790M)."  Fukui (8).
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B. Rationale for Testing and Characteristics of the T790 Mutation
0 Q/ j# l' Y# @: p1 GThe T790m mutation plays an important but not exclusive role in generating resistance to Tarceva.  It makes sense to determine its impact upon a particularly patient.   See gxsgenetyping.com<http://gxsgenetyping.com/> outlining its T790 test.  It may make sense to test patients taking Tarceva yearly for the mutation, or at least when it appears Tarceva is no longer effective.

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( |' i2 Q& p. @; q" v$ ["The T790M test uses a combination of Scorpions&reg; and ARMS&reg; (allele specific PCR) technology. This approach allows the development of very sensitive tests that can detect mutations in a background of normal cells. The real-time PCR based test enables rapid identification and quantification of the mutations. Mutations can be detected at a ratio of 1:100 mutant: normal DNA and this allows the kit to detect genetic variation that could not be detected using DNA sequencing methods." dxsgenotyping.com<http://dxsgenotyping.com/>
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III. Pan-Inhibitors
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A. Overall Approach
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Pan-inhibitors have shown some success in cell studies in suprresing T790 resistance. Sharma explains:


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. V2 D' n9 j; q3 r6 X- @"one of the main challenges in the treatment of NSCLC is to design inhibitors that can overcome the steric interference to drug binding conferred by the T790M mutation. Irreversible inhibitors seem to show some promise in this regard. In most cases, irreversible inhibitors form a covalent bond with crucial cysteine residues — Cys797 within EGFR or Cys805 within ERBB2 — in the active site of the respective enzymes. Given the fact that only EGFR and ERBB2 (as opposed to ERBB4) have cysteines at these corresponding positions, irreversible ErbB inhibitors show very high specificity for EGFR and ERBB2. Previous studies from our laboratory have shown that the irreversible dual EGFR and ERBB2 inhibitors, HKI-272 (Ref. 136) and HKI-357 (Ref. 37), as well as the irreversible EGFR inhibitor EKB-569 (Ref. 137) were all able to overcome gefitinib resistance owing to T790M in cis with an L858R mutation in EGFR. Sharma (5)

"Pan  inhibitors permanently and irreversibly stop certain functioning of EGFR.   Initial cell studies have indicated these stronger inhibitors can work against the resistant cells with the mutation.  To determine whether the T790M mutation leads to resistance to EGFR inhibitors that have different molecular structures and mechanisms, we screened four commercially available EGFR inhibitors (AG1478, cetuximab, erlotinib, and CL-387,785) using cells that were transiently transfected with the delL747–S752 construct and the delL747–S752+ T790M construct. We consistently found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, strongly inhibited EGF-induced phosphorylation  While this may not be a valid alternative for many patients, it may make sense for patients whose cancers have been shown to be associated with EGFR."
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' ~8 d4 J+ F0 l, ]8 P"Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells.... Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation."  Kubayashi
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Its success in human studies has been debatable.  There have been several trials but none sufficient impressive to move towards FDA approval.  Many of these studies did not deal solely with T790M but a variety of patients.  Part of the problem may be the company's desire to secure aa drug that is effective overall, and reports testing for the T790M mutation and detailing the drug's impact are strangely difficult to find.
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B. HKI 272


One cell study found pan-inhibitor HKI 272 effective with tumor cells in a laboratory setting. "HKI 272 is effective in inhibiting various lung cancer mutations- "HKI-272 is effective in growth inhibition of Ba/F3 cells transformed with EGFRvIII, EGFR-L858R, and EGFR-L858R-T790M."   Ji (1)


+ w7 ?( A2 v: L5 QC. Lapanatib

6 V2 h" t; S! i3 Z& H9 A" {A recent study showed promise for a combination of Cetuximab (Erbitux) and Lapatanib (Tykerp),
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"In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC."
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) ~. z6 ^6 Y, \0 v4 F; VBoth Erbitux and Lapatanib are FDA approved drugs, though not specifically approved for this purpose.  They can be prescribed off label if a physician chooses.

D. Zactima (ZD-6474)
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& ^9 T) s! I, M$ VE. BMS 690514

5 N9 o( i2 D7 I' ~% S3 d, LOnly cell studies are available.  "BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation."

! P/ S6 ]# o; X4 U以下是通过谷歌翻译的上述资料
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9 c* k* r4 r; {4 K0 b, Q$ G     另外，泛抑制剂（泛 - 抑制剂=多靶位抑制剂）。有点用目前，有效的抵抗特罗凯抗药性的方法是同时用两个药，跺抑制剂加上爱必妥（爱必妥） 。
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“电阻与表皮生长因子受体定向治疗treatmentA关键问题是，一段时间后，经常8-12个月，癌细胞产生耐药性的治疗。阻力的主要来源是称为第二次突变T790M。 [16]的阻力的第二个来源是MET的基因突变。
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# U: Z9 [: G6 O. \化学电阻发生招聘突变的IGF - 1受体作为表皮生长因子受体的二聚体伙伴之一，因此形成异源二聚体[17]这使得即使在EGFR抑制剂的存在传输信号。有些IGR - 1R抑制剂在不同的发展阶段（根据各地如AG1024或AG538 tyrphostins [18]或吡咯并[2,3 - D]嘧啶衍生物，如NVP - AEW541 [19]）。

泛抑制剂显示了一些打击抵抗，至少在细胞研究的承诺。今天（3 / 10）最有前途的方法来打击抵抗似乎是一个双管齐下的办法，像272港岛与Erbitux的结合泛抑制剂。 “令人惊讶的是，我们发现，只有这两种药物的结合在了一起诱导厄洛替尼抗肿瘤窝藏T790M突变的戏剧性的收缩，因为他们一起有效耗尽表皮生长因子受体磷酸化和总，我们建议，这些研究有立即肺癌患者的治疗意义双与西妥昔单抗（爱必妥）和第二代EGFR TKI的目标可能是一种有效的策略，以克服T790M介导的耐药性。“双针对表皮生长因子受体，可以克服在EGFR突变肺癌的小鼠模型的主要耐药性突变[20]“

另一篇专门讲怎样战胜特罗凯抗药性的文章。不知中国能否找到跺抑制剂HKI - 272和爱必妥（后者应当好找）。

) N- Q3 P1 F2 H/ [ 寻址厄洛替尼电阻
一，概述和背景

A.表皮生长因子受体和肺癌
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- a* D. d: c4 e5 c9 d人体细胞与基因重复这个过程的正常部分之间的信号有一个复杂的系统。复制增长，修复受损细胞和其他职能所必需的，基因信号启动复制的其他细胞。在信号故障是癌症的重要组成部分和酪氨酸激酶是一个重要的的目标：
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对肿瘤细胞的失控扩散是癌症的一个标志。在许多类型的癌症，激活细胞信号转导通路中的基因突变有助于增强增殖和癌细胞的存活。一个良好的特点的例子是在酪氨酸激酶的突变，调节细胞的生长和生存的酶，。酪氨酸激酶活性，在正常细胞中紧密监管，但由于在某些癌症，包括肺癌的突变失调，增强癌细胞的扩散和生存。酪氨酸激酶分子靶向治疗癌症的有吸引力的候选人，因为癌症成为依赖于酪氨酸激酶突变的增长信号。酪氨酸激酶需要三磷酸腺苷，其酶活性，从而模仿ATP小分子可以结合激酶突变体灭活他们inveas增长因素的致癌细胞过度重复提示。克拉克（6）

8 D$ P# n: v1 I肺癌患者的分组已经在表皮生长因子受体（EGFR），这是与各种形式的癌症，特别是肺癌关联的突变。 Vikis（2）。 “最近的工作已经确定了一系列的体细胞突变外显子18至21表皮生长因子（EGF）受体（EGFR），使肺肿瘤反应的吉非替尼和厄洛替尼疗法。” Vikis（2）。这些人EGFR阳性，作为衡量一个敏感的EGFR突变试验。见哈佛EGFR的测试。

特罗凯是表皮生长因子受体阳性的患者反应率约60％，反应率进一步后，特别是外显子（S）上的突变位于不同。 EGFR阳性患者主要但不完全非吸烟者，腺癌。一些清淡的前烟民和一些鳞状细胞癌患者EGFR阳性。 EGFR阳性的患者会出现异常EGFR信号驱动的肿瘤。与癌基因瘾，一个似是而非的理论。
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$ e: r9 q, g; \: b6 ?) oEGFR是雇员再培训局的受体家族的一部分。包括Erb2在内的其他受体之间的交叉信号时，虽然其他受体在肺癌的确切作用目前还不清楚。
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虽然特罗凯的初步反应率是令人印象深刻的部分甚至完全反应，（彻底消除任何可见的肿瘤CT上的药物），许多患者产生耐药性和Tarceva生效。为什么患者产生耐药性，我们能做些什么问题。
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二。 T790M突变的发展
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6 H/ ^& U1 p$ f* D3 |A. T790突变
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) h, t  S+ `# S" ?* R然而，许多患者的初步回应，以特罗凯药物不再有效。原因似乎是在T790M特罗凯抗EGFR突变的发展。 “使用酪氨酸激酶抑制剂（TKI）治疗肺腺癌已经取得了巨大的成功。，但是，谁开发的抗TKI治疗的患者往往获得一个体抗突变（T790M）位于表皮生长因子受体的催化裂（表皮生长因子受体）的酶。“ Vikis（2）。 “的患者，经药物治疗的进展，它已被观察到，往往是次要的”抵抗“突变外显子20（4-6）收购。这种突变，T790M，出现在这些案件的50％somatically。” Vikis（2）。更改涉及苏氨酸，蛋氨酸替代的表皮生长因子受体（EGFR）基因的氨基酸位置790（T790M）。“犬养（3）。”约有一半的获得性耐药的EGFR - TKIs的，几乎总是发生在在治疗过程是一个在密码子790（T790M）中学突变引起的。“福井（8）。
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# h+ s8 m( y/ e& A% y! m* v8 K7 tB.测试的基本原理和T790突变的特点

% x' p, y) J3 v7 k) Q" \  xT790M突变起着重要但不是唯一的作用产生抵抗特罗凯。这是有道理的，以确定其影响时特别门诊。见gxsgenetyping.com <http://gxsgenetyping.com/>概述T790测试。它可能使患者服用特罗凯的突变每年的测试，或至少在出现特罗凯不再有效。

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$ r9 X/ D: W' L( x0 A# \“T790M测试使用相结合的蝎子&reg;和武器&reg;（等位基因特异性PCR）技术，这种方法允许发展非常敏感的测试，可以检测在正常细胞的背景基因突变。实时PCR为基础的测试，可以快速识别和定量基因突变的突变可以发现：正常的DNA突变的比例为1:100，这使得试剂盒检测不能使用的DNA测序方法检测的遗传变异“。 dxsgenotyping.com <http://dxsgenotyping.com/>

8 ]7 z! R; U2 F三。泛抑制剂
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A.总体方针
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泛抑制剂suprresing T790电阻细胞研究取得了一些成功。夏尔马解释：
  t5 o, W2 I. V8 y" \8 n! J/ C “在非小细胞肺癌治疗的主要挑战之一是设计抑制剂，可以克服T790M突变所赋予的药物结合的立体干扰，不可逆抑制剂似乎在这方面表现出一定的承诺，在大多数情况下，不可逆抑制剂形成一个共价内表皮生长因子受体或Cys805 Cys797内ERBB2 - - 至关重要的半胱氨酸残基债券，在各自的酶的活性部位，鉴于这一事实，只有EGFR和ErbB2（反对ERBB4）有相应的岗位在这些半胱氨酸，不可逆转的ERBB抑制剂表现出非常高的特异性EGFR和ERBB2从我们实验室以前的研究已经表明，不可逆的双表皮生长因子受体和ErbB2抑制剂HKI - 272（编号136）和HKI - 357（编号37），以及不可逆的EGFR抑制剂EKB - 569 （编号137）都是能够克服在独联体国家中在EGFR L858R突变与吉非替尼抵抗由于到T790M的。夏尔马（5）