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

项目摘要 靶向治疗彻底改变了转移性肺肿瘤的诊断和治疗前景 癌尽管取得了这一成功，但靶向治疗并不具有治愈性，获得性耐药是主要的治疗方法。 阻碍用这些疗法治疗的患者的治愈或持久反应。一个范例， 肺癌靶向治疗的成功，来自表皮生长因子受体（EGFR）突变 肺癌在编码EGFR酪氨酸激酶结构域的外显子中的突变在大约10- 20个基因中被发现。 美国15%的肺腺癌。这些突变赋予对酪氨酸激酶抑制剂（TKI）的敏感性 四种TKI（厄洛替尼、吉非替尼、阿法替尼和最近的奥希替尼）目前已获批用于一线治疗 EGFR突变型肺癌的治疗。然而，获得性耐药性是所有这些药物的主要挑战 TKI包括奥希替尼，但我们对耐药机制的了解非常有限。 奥希替尼最近被临床采用。如果不了解耐药机制， 奥希替尼治疗后的治疗策略仍有待确定。我们实验室和其他机构的数据表明， 奥希替尼耐药可通过EGFR依赖性机制产生，涉及几种不同类型的 EGFR突变和EGFR非依赖性机制-通常是表观遗传起源-是很差的 明白关于这些耐药机制的分子背景知之甚少 它们的出现频率，生物化学以及如何瞄准它们。考虑到 采用奥希替尼作为一线治疗，迫切需要确定这些机制， 漏洞我们建议利用我们在肺癌生物学，小鼠模型， 靶向治疗的耐药性和EGFR结构生物学来解决这些问题。使用独特的体外和 奥希替尼获得性耐药的体内模型和患者资源，创新的基因组和生物化学 我们将使用的工具：1）确定奥西替尼耐药EGFR的分子特征和新的治疗漏洞 变体。2)建立突变型EGFR异源二聚化模式，并确定这些模式是否可以利用 3）鉴定赋予TKI抗性的表观遗传过程。 我们的研究将产生对奥希替尼耐药性的全面了解和发展洞察力 靶向奥希替尼耐药肿瘤的新机制方法-一个迫切的未满足的临床需求。

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.