Drug Resistance in Lung Cancer

描述(由申请人提供)：非小细胞肺癌(NSCLC)的致癌基因组改变是很好的治疗靶点。引人注目的临床例子包括表皮生长因子受体(EGFR)和间变性淋巴瘤激酶(ALK)重排的体细胞突变。在这两种情况下，与系统化疗相比，使用特定的激酶抑制剂erlotinib(EGFR)和crizotinib(ALK)可以改善晚期EGFR突变或ALK重排NSCLC患者的结果，并且是护理一线治疗的标准。然而，治疗的益处是有限的(8至12个月)：目前没有患者被治愈，所有患者最终都会产生获得性耐药性。对激酶抑制剂产生耐药性的机制有两种：一是激酶靶标的继发性突变，二是旁路信号通路的激活。在这两种情况下，下游信号通路被重新激活，尽管存在激酶抑制剂。在EGFR突变的非小细胞肺癌中，EGFR T790M继发突变是最常见的机制，在临床上对厄洛替尼产生耐药性的EGFR突变患者的癌症中检测到50%-60%。旁路机制包括MET的激活(通过MET扩增或HGF)和Axl信号。到目前为止，对耐药非小细胞肺癌患者的EGFR突变埃洛替尼的临床治疗一直无效。这些观察结果很可能是由于：1)缺乏有效的治疗方法 针对EGFR T790M的药物，ii)对患者耐药的异质性了解不完全，以及iii)无法制定同时抑制多种耐药机制的策略。我们之前已经证明，在使用不可逆转的EGFR抑制剂的临床前模型中，我们可以克服EGFR T790M突变带来的耐药性。然而，目前临床上不可逆的喹唑啉EGFR抑制剂，包括阿法替尼和达科米替尼，尽管在一些携带EGFR T790M的临床前模型中有效，但对EGFR T790M非小细胞肺癌患者无效。这些观察结果的一个可能的解释可能在于这样一个事实，即阿法替尼和达科米替尼是非常好的野生型(WT)EGFR的抑制剂。因此，抑制WT EGFR会导致“靶向”毒性，即皮疹，这会阻止临床使用足够高的剂量来抑制EGFR T790M。为了克服这一限制，我们开发了两种临床前策略：i.)间歇“脉冲式”给药达科米替尼，暂时但有效地抑制EGFR T79M和II。)第一个突变型选择性EGFR抑制剂WZ4002的鉴定。这两种策略目前都在临床试验中进行评估。在这里，我们建议进行批判性研究 这将通过全面研究耐药机制的异质性，开发与了解耐药机制的WZ4002的新组合策略，以及开发基于临床试验的生物标记物来改进对耐药演变和治疗的评估，从而为这些和未来治疗策略的临床发展提供信息。

DESCRIPTION (provided by applicant): Oncogenic genomic alterations in non-small cell lung cancer (NSCLC) are excellent therapeutic targets. Compelling clinical examples include somatic mutations in the epidermal growth factor receptor (EGFR) and in anaplastic lymphoma kinase (ALK) rearrangements. In both instances, treatment with specific kinase inhibitors, erlotinib (EGFR) and crizotinib (ALK), results in improved outcomes compared to systemic chemotherapy for patients with advanced EGFR mutant or ALK rearranged NSCLC, and are the standard of care first line therapies. However, the therapeutic benefit is limited (8 to 12 months): currently no patient is cured and all patients wll ultimately develop acquired drug resistance. Drug resistance to kinase inhibitors occurs by two types of mechanisms: i) secondary mutations in the kinase target or ii) activation of a bypass signaling pathway. In both cases, downstream signaling pathways become reactivated despite the presence of the kinase inhibitor. In EGFR mutant NSCLC, EGFR T790M secondary mutation is the most common mechanism, detected in 50-60% of cancers from EGFR mutant patients that develop clinical resistance to erlotinib. Bypass mechanisms include activation of MET (through MET amplification or by HGF) and AXL signaling. To date, clinical therapies for EGFR mutant erlotinib resistant NSCLC patients have been ineffective. These observations are likely due to i) lack of effective therapeutic agents against EGFR T790M, ii) incomplete understanding of the heterogeneity of drug resistance in patients, and iii) inability to develop strategies to inhibit multiple drug resistane mechanisms simultaneously. We have previously shown that we can overcome resistance conferred by EGFR T790M mutations in preclinical models with irreversible EGFR inhibitors. However, current clinical irreversible quinazoline EGFR inhibitors, including afatinib and dacomitinib, although effective in some preclinical models harboring EGFR T790M, are not effective in EGFR T790M NSCLC patients. One possible explanation for these observations may lie in the fact that afatinib and dacomitinib are very good inhibitor of wild type (WT) EGFR. As such, inhibition of WT EGFR results in "on-target" toxicity, skin rash, which prevents clinical administration of doses high enough to inhibit EGFR T790M. In order to overcome this limitation, we have developed two pre-clinical strategies: i.) intermittet "pulsatile" administration of dacomitinib to transiently but effectively inhibit EGFR T79M and ii.) identification of the first in class mutant selective EGFR inhibitor, WZ4002. Both strategies are currently being evaluated in clinical trials. Here we propose critical studies that will inform the clinical development of these and future treatment strategies by comprehensively studying heterogeneity of drug resistance mechanisms, developing novel combination strategies with WZ4002 informed by drug resistance mechanisms, and developing clinical trial-based biomarkers for improved evaluation of the evolution and treatment of drug resistance.