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

摘要 非小细胞肺癌占全世界癌症相关死亡人数最多， 目前严重缺乏晚期疾病患者的治疗选择。肺癌 腺癌是最常见的组织学亚型，通常在表皮细胞中具有激活突变。 生长因子受体（EGFR），可以用酪氨酸激酶抑制剂（TKI）治疗;然而，这 治疗不是治愈性的。随着最近FDA批准奥希替尼， 一种MUR特异性第三代EGFR TKI，作为晚期EGFR突变型非小细胞肺癌的一线治疗 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- 与第一代EGFR TKI治疗患者的10个月相比，这些患者的无瘤生存期更短。 目前还没有批准的治疗策略来克服对奥希替尼的耐药性，这突出了 需要新的策略来提高患者的生存率。然而，对这些机制知之甚少。 对一线奥希替尼的获得性耐药，必须在最佳二线治疗前进行探索 可以制定战略。我们假设对一线奥希替尼的耐药主要是由 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敏感。我们的假设是基于：1）公布的数据， 细胞系显示EGFR中的继发性突变对第一和第二突变的敏感性不同， 第二代EGFR TKI和2）我们实验室的初步工作表明， 基于存在的特异性突变，在体内对其他TKI的应答不同。为了实现我们的目标，我们 建议进一步揭示一线奥希替尼获得性耐药的机制，以及 或者说是抵抗的信号基础此外，我们将确定这些继发性EGFR的敏感性， 其他EGFR TKI的突变及其赋予耐药性的方法。

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.