Drug Resistance in Lung Cancer

描述（由申请方提供）：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）吉非替尼和厄洛替尼是治疗肿瘤携带EGFR体细胞激活突变的非小细胞肺癌（NSCLC）患者的有效治疗药物。然而，所有最初出现显著临床反应的患者在接受吉非替尼或厄洛替尼治疗时，最终都会出现肺癌的进行性生长。已经确定了两种已知的获得性（或继发性）抗性机制。其中包括50%的患者发生的EGFR自身继发突变（EGFR T790 M）和20%的患者发生的MET癌基因扩增。包括不可逆EGFR抑制剂和EGFR/MET抑制剂联合治疗以克服这些继发性耐药机制的治疗策略已在临床前进行了评估，目前正在进入临床开发阶段。然而，关于耐药性发展的几个基本问题仍然没有答案。首先，特定的吉非替尼耐药克隆是预先存在的，因此在治疗过程中被选择，还是在吉非替尼治疗过程中出现？第二，虽然第二代激酶抑制剂可能具有治疗益处，但完全可以预期也会对这些药物产生耐药性（三级耐药性）。我们使用EGFR突变NSCLC细胞系在体外模拟了EGFR激酶抑制剂的耐药性。重要的是，这些吉非替尼耐药EGFR突变NSCLC细胞系与临床上发生吉非替尼或厄洛替尼耐药的EGFR突变NSCLC患者的肿瘤产生相同的耐药机制，我们使用这种体外模型系统鉴定了先前未被怀疑的吉非替尼耐药新机制（MET扩增）。因此，这些细胞系提供了一个强大的体外系统，其中研究吉非替尼耐药性的起源，并确定第二代疗法是否可能改变或延迟吉非替尼耐药性的发生。此外，它们可用于进一步确定对不可逆EGFR抑制剂和/或EGFR/MET抑制剂组合的三级耐药机制。细胞系模型的结果将用于检查来自EGFR突变患者的肿瘤标本，这些患者正在接受吉非替尼、厄洛替尼或第二代激酶抑制剂的临床试验治疗。这些研究将通过以下具体目标来完成：目标1：确定吉非替尼耐药克隆是否预先存在或在药物治疗期间重新出现。目的2：确定中和已知吉非替尼耐药机制的治疗剂如何影响耐药性的出现。目的3：探讨EGFR突变型NSCLC的三级耐药机制。临床前研究可能会为EGFR突变型NSCLC患者带来新的治疗模式，有望使EGFR靶向治疗的获益持续时间比目前更长。表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）吉非替尼和厄洛替尼是治疗EGFR基因改变（突变）的肺癌患者亚群的有效疗法。不幸的是，所有患者最终都会对这些药物产生耐药性。然而，第二代治疗剂已经针对特定的吉非替尼耐药机制而开发。该提案的目标是在体外研究耐药机制，并使用EGFR突变的肺癌患者的肿瘤。公共卫生相关性：概述的研究将侧重于吉非替尼/厄洛替尼耐药的基本机制，开发最有效的策略来延迟或预防吉非替尼/厄洛替尼耐药的出现，并确定对第二代治疗药物的耐药机制。这些研究的结果将有望导致与EGFR靶向治疗的获益持续时间比目前更长相关的治疗方法。该提案的研究结果将对EGFR突变型NSCLC的治疗产生重大影响。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective therapeutic agents for patients with non-small cell lung cancer (NSCLC) whose tumors harbor somatic activating mutations in EGFR. However, all patients who initially develop dramatic clinical responses will ultimately develop progressive growth of their lung cancer while being treated with gefitinib or erlotinib. Two known mechanisms of acquired (or secondary) resistance have been identified. These include a secondary mutation in EGFR itself (EGFR T790M) occurring in 50% of patients and amplification of the MET oncogene in 20% of patients. Therapeutic strategies including irreversible EGFR inhibitors and the combination of EGFR/MET inhibitors to overcome these secondary resistance mechanisms have been evaluated pre-clinically and are now entering clinical development. However, several fundamental questions regarding the development of resistance remain unanswered. First, do specific gefitinib resistant clones pre-exist and are thus selected for during the course of therapy or do they arise during the course of gefitinib treatment? Second, while second generation kinase inhibitors are likely to have a therapeutic benefit, it is fully anticipated that resistance (tertiary resistance) will also develop to these agents. We have modeled resistance to EGFR kinase inhibitors in vitro using EGFR mutant NSCLC cell lines. Importantly, these gefitinib resistant EGFR mutant NSCLC cell lines develop the same mechanisms of resistance as do tumors from NSCLC patients with EGFR mutations who clinically develop gefitinib or erlotinib resistance and we have used this in vitro model system to identify a previously unsuspected novel mechanism of gefitinib resistance (MET amplification). Thus these cell lines provide a powerful in vitro system in which to study the origins of gefitinib resistance and to determine whether second generation therapies might alter or delay the onset of gefitinib resistance. In addition, they can be used to further determine the mechanisms of tertiary resistance to irreversible EGFR inhibitors and/or to the combination of EGFR/MET inhibitors. Findings from the cell line models will then be used to examine tumor specimens from patients with EGFR mutations who are being treated in clinical trials with gefitinib, erlotinib or second generation kinase inhibitors. These studies will be accomplished through the following specific aims: Aim 1: To determine whether gefitinib resistant clones pre-exist or arise de novo during drug treatment. Aim 2: To determine how therapeutic agents that neutralize known gefitinib resistance mechanisms impact the emergence of drug resistance. Aim 3: To determine mechanisms of tertiary drug resistance in EGFR mutant NSCLC. The pre-clinical studies will likely lead to new treatment paradigms for patients with EGFR mutant NSCLC which will hopefully be associated with an even longer duration of benefit from EGFR targeted therapy than currently achievable. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective therapies for subsets of lung cancer patients whose cancers harbor genetic alterations (mutations) in EGFR. Unfortunately, all patients ultimately develop resistance to these drugs. However, second generation therapeutic agents have been developed against specific gefitinib resistance mechanisms. The goal of this proposal is to study drug resistance mechanisms in vitro and using tumors from lung cancer patients with EGFR mutations. PUBLIC HEALTH RELEVANCE: The outlined studies will focus on fundamental mechanisms of gefitinib/erlotinib resistance, on developing the most effective strategy to delay or prevent the emergence of gefitinib/erlotinib resistance and on identifying the mechanisms of resistance to second generation therapeutic agents. The findings from these studies will hopefully lead to treatment approaches that will be associated with an even longer duration of benefit from EGFR targeted therapy than currently achievable. Together findings from this proposal will have major impact in the treatment of EGFR mutant NSCLC.