Project 2: Mechanism-based approaches to counter TKI resistance in EGFR mutant lung cancer

项目总结 靶向治疗彻底改变了转移性肺的诊断和治疗格局 癌症。尽管取得了这样的成功，但靶向治疗并不能治愈，获得性耐药性是一个主要原因 对接受这些疗法治疗的患者的治愈或持久反应的障碍。一种适用于 肺癌靶向治疗的成功来自于表皮生长因子受体(EGFR)突变 肺癌。编码EGFR酪氨酸激酶结构域的外显子突变在大约10- 美国15%的肺腺癌。这些突变使人对酪氨酸激酶抑制剂(TKI)敏感 四种TKI(厄洛替尼、吉非替尼、阿法替尼和最近的奥西美替尼)目前被批准用于一线 EGFR突变型肺癌的治疗。然而，获得性耐药性是所有这些疾病的主要挑战。 TKI包括奥西莫替尼，但我们对其耐药机制的了解非常有限 奥西莫替尼最近在临床上被采用。在不了解抗性机制的情况下，最佳 奥西美替尼后的治疗策略仍有待确定。来自我们实验室和其他机构的数据表明 奥西美替尼耐药可通过两种EGFR依赖机制发生，涉及几种不同类型的 EGFR突变和EGFR非依赖性机制--通常起源于表观遗传--很差 明白了。对这些抗性机制的分子背景(S)知之甚少 它们的出现、它们的频率、生物化学以及如何从药理上针对它们。鉴于……的速度 采用奥西美替尼作为一线治疗，迫切需要确定这些机制和结果 漏洞。我们建议利用我们在肺癌生物学、小鼠模型、 抵抗靶向治疗和EGFR结构生物学来解决这些问题。使用独特的体外和 奥西美替尼获得性耐药的体内模型和患者资源、创新的基因组和生化 我们将使用的工具：1)确定耐奥西美替尼的EGFR的分子特征和新的治疗脆弱性 变种。2)建立突变的EGFR异二聚化模式，并确定是否可以利用这些模式 从治疗上克服奥西莫替尼耐药；3)确定赋予TKI耐药的表观遗传过程。 我们的研究将产生对奥西美替尼耐药性的全面理解和发展的洞察力 针对奥西美替尼耐药肿瘤的基于机制的新方法--一个迫切的未得到满足的临床需求。

PROJECT SUMMARY Targeted therapies have completely transformed the landscape for diagnosis and treatment of metastatic lung cancer. Despite this success, targeted therapies are not curative and acquired resistance is a major impediment to cures or durable responses for patients treated with these therapies. A paradigm for the success of targeted therapies in lung cancer, comes from Epidermal Growth Factor Receptor (EGFR) mutant lung cancer. Mutations in exons encoding the tyrosine kinase domain of EGFR are found in approximately 10- 15% of lung adenocarcinomas in the US. These mutations confer sensitivity to tyrosine kinase inhibitors (TKIs) and four TKIs (erlotinib, gefitinib, afatinib and, most recently, osimertinib) are currently approved for the first-line treatment of EGFR mutant lung cancer. Acquired drug resistance, however, is a major challenge with all of these TKIs including osimertinib, but we have very limited knowledge of the mechanisms of resistance to osimertinib given its recent adoption in the clinic. Without knowledge about resistance mechanisms, optimal post-osimertinib treatment strategies remain to be defined. Data from our labs and others indicate that osimertinib resistance can arise through both EGFR-dependent mechanisms involving several different types of EGFR mutation and EGFR-independent mechanisms – frequently epigenetic in origin – that are poorly understood. Very little is known about the molecular context(s) in which these resistance mechanisms emerge, their frequency, biochemistry and how to target them pharmacologically. Given the speed of adoption of osimertinib as 1st line therapy, there is an urgent need to identify these mechanisms and resulting vulnerabilities. We propose to leverage our collective expertise in lung cancer biology, mouse models, resistance to targeted therapies and EGFR structural biology to address these issues. Using unique in vitro and in vivo models and patient resources of acquired resistance to osimertinib, innovative genomic and biochemical tools we will: 1) Identify molecular features and new therapeutic vulnerabilities of osimertinib-resistance EGFR variants. 2) Establish mutant EGFR heterodimerization patterns and determine whether these can be leveraged therapeutically to overcome osimertinib resistance; 3) Identify epigenetic processes that confer TKI resistance. Our studies will yield a comprehensive understanding of osimertinib resistance and insight with which to develop new mechanism-based approaches to target osimertinib-resistant tumors – an urgent unmet clinical need.