INVESTIGATING ACQUIRED RESISTANCE TO FIRST-LINE OSIMERTINIB IN EGFR MUTANT MODELS OF LUNG ADENOCARCINOMA

摘要 非小细胞肺癌占全球与癌症相关的死亡人数最多，而且有 目前，严重缺乏晚期疾病患者的治疗选择。肺病患者 腺癌是最常见的组织学亚型，通常在表皮中有激活突变。 生长因子受体(EGFR)，可以用酪氨酸激酶抑制剂(TKIs)治疗；然而，这 治疗是不能治愈的。随着FDA最近批准奥西美替尼，一种新的治疗范例正在出现， 突变特异性第三代EGFR TKI作为晚期EGFR突变非小细胞的一线治疗 肺癌患者。一项正在进行的临床试验的最新数据显示，19个月的进展令人印象深刻- 与接受第一代EGFR TKI治疗的患者相比，这些患者的自由生存期为10个月。 目前还没有批准的治疗策略来克服对奥西美替尼的耐药性，这突显了 需要新的策略来提高患者的存活率。然而，人们对其发病机制知之甚少。 对一线奥西美替尼的获得性耐药性，必须在最佳二线治疗之前进行探索 战略是可以制定的。我们假设对一线奥西美替尼的耐药性主要是通过 通过EGFR的继发性突变，具有这些突变的肿瘤表现出不同的模式 对第一代或第二代EGFR TKI的敏感性。我们的假设是基于：1)来自 显示EGFR的继发性突变对第一和第二不同敏感的细胞系 生成EGFR TKIs和2)我们实验室的初步工作表明，奥西美替尼耐药肿瘤 根据存在的特定突变，在体内对其他TKI有不同的反应。为了实现我们的目标，我们 建议进一步揭示对一线奥西美替尼的获得性耐药机制及生化 或这种抗性的信号基础。此外，我们将确定这些次级EGFR的敏感性 突变到其他EGFR TKI以及它们产生耐药性的方法。

ABSTRACT Non-small cell lung cancer accounts for the most cancer-related deaths worldwide and there is currently a severe lack of treatment options for patients with advanced-stage disease. Patients with lung adenocarcinoma, the most common histological subtype, often have activating mutations in the Epidermal Growth Factor Receptor (EGFR) and can be treated with tyrosine kinase inhibitors (TKIs); however, this treatment is not curative. A new treatment paradigm is emerging with the recent FDA approval of osimertinib, a mutant-specific third generation EGFR TKI, as a first-line therapy for advanced EGFR mutant non-small cell lung cancer patients. Recent data from an ongoing clinical trial shows an impressive 19-month progression- free survival in these patients, compared with 10 months in patients treated with a first generation EGFR TKI. There are currently no approved therapeutic strategies to overcome resistance to osimertinib, highlighting the need for novel strategies to improve patient survival. However, very little is known about the mechanisms of acquired resistance to first-line osimertinib and this must be explored before an optimal second-line treatment strategy can be developed. We hypothesize that resistance to first-line osimertinib is mediated primarily through secondary mutations in EGFR, and tumors with these mutations exhibit different patterns of sensitivity to first or second generation EGFR TKIs. Our hypothesis is based on: 1) published data from cell lines showing that the secondary mutations in EGFR are differentially sensitive to first and second generation EGFR TKIs and 2) preliminary work from our lab indicating that osimertinib-resistant tumors differentially respond to other TKIs in vivo based on the specific mutation present. To achieve our goal, we propose to further uncover the mechanisms of acquired resistance to first-line osimertinib and the biochemical or signaling basis of this resistance. Additionally, we will establish the sensitivity of these secondary EGFR mutations to other EGFR TKIs and the method through which they confer their resistance.