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极好的治疗靶点。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，与晚期EGFR突变或ALK重排的NSCLC患者的全身化疗相比，使用特异性激酶抑制剂厄洛替尼（EGFR）和克唑替尼（ALK）治疗可改善预后，并且是一线治疗的标准。然而，治疗效益有限（8至12个月）：目前没有患者治愈，所有患者最终都会产生获得性耐药。对激酶抑制剂的耐药性通过两种机制发生：1)激酶靶点的继发性突变或2)旁路信号通路的激活。在这两种情况下，尽管存在激酶抑制剂，下游信号通路仍被重新激活。在EGFR突变的NSCLC中，EGFR T790M继发性突变是最常见的机制，在50-60%的EGFR突变患者中检测到对厄洛替尼产生临床耐药的癌症。旁路机制包括MET的激活（通过MET扩增或HGF）和AXL信号。迄今为止，EGFR突变厄洛替尼耐药NSCLC患者的临床治疗无效。这些观察结果可能是由于i)缺乏有效的治疗方法

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.