Non-genomic resistance mechanisms in EGFR-mutant lung cancer

项目摘要 Osimertinib是第三代EGFR酪氨酸激酶抑制剂(TKI)，是目前一线治疗的标准药物 EGFR突变肺癌患者的治疗。虽然奥西美替尼在诱导肿瘤退化方面是有效的， 对于大多数患者来说，提高生活质量和延长生存时间是不能治愈的。获得性的早期研究 耐药性表明，即使在对耐药性机制进行了标准的组织学和基因组评估之后， 奥西莫替尼耐药的很大一部分仍未确定。这种不完整的理解 奥西美替尼耐药是临床开发新的有效治疗方法的重要障碍。我们 假设与上一代EGFR抑制剂相反，非基因组机制正在推动 大多数获得性耐药对一线奥西美替尼。到目前为止，对EGFR TKI的评估获得了耐药性 机制一直集中在基因组耐药突变、扩增和融合上，部分原因是这些 在肿瘤组织或基于血液的ctDNA液体活检中很容易检测到。在这个项目中，我们试图 发现非基因组的osimertinib耐药谱。我们的主要目标是确定两种肿瘤的内在 奥西美替尼耐药机制及肿瘤外源性微环境耐药机制。在……里面 目的1，我们将使用一种新的基于血液的检测方法Rare-Seq来定量检测肿瘤基因的表达模式。 复发的EGFR突变非小细胞肺癌患者对奥西美替尼的耐药性。在目标2中，我们将研究肿瘤细胞 通过利用我们强大的翻译基础设施来开发奥西美替尼耐药的外部机制 奥西美替尼耐药活检的癌症相关成纤维细胞模型。我们将使用这些模型来剖析 CAF、肿瘤细胞和免疫细胞之间的功能相互作用，我们将把这些结果与 临床活检的空间分子分析。总的来说，这项提案中描述的研究将产生一个 全面了解奥西美替尼的耐药性，并为未来治疗方法的发展奠定基础 克服对奥西莫替尼的耐药性。

Project Summary Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is the current standard of care for first-line therapy for EGFR mutant lung cancer patients. While osimertinib is effective in inducing tumor regressions, improving quality of life and prolonging survival in most patients, it is not curative. Early studies of acquired resistance suggest that even after standard histologic and genomic assessments for resistance mechanisms, a substantial portion of osimertinib resistance remains uncharacterized. This incomplete understanding of osimertinib resistance poses a significant barrier to developing new and effective therapies for clinical use. We hypothesize that, in contrast to earlier generation EGFR inhibitors, non-genomic mechanisms are driving the majority of acquired resistance to first-line osimertinib. To date, assessments of EGFR TKI acquired resistance mechanisms have focused on genomic resistance mutations, amplifications, and fusions, in part because these can be readily detected in tumor tissue or in blood-based ctDNA liquid biopsies. In this project we seek to discover the spectrum of non-genomic osimertinib resistance. Our main objective is to identify both tumor intrinsic mechanisms of osimertinib resistance as well as tumor extrinsic microenvironmental resistance mechanisms. In Aim 1, we will use RARE-Seq, a novel blood-based assay to quantify tumor gene expressions patterns of resistance in EGFR mutant NSCLC patients relapsing on osimertinib. In Aim 2, we will investigate tumor cell extrinsic mechanisms of osimertinib resistance by leveraging our robust translational infrastructure to develop cancer-associated fibroblast models from osimertinib resistance biopsies. We will use these models to dissect functional interactions between CAFs, tumor cells and immune cells, and we will integrate these results with spatial molecular analysis of clinical biopsies. Collectively, the studies described in this proposal will generate a comprehensive picture of osimertinib resistance and set the stage for future development of therapies that overcome resistance to osimertinib.