Non-genomic resistance mechanisms in EGFR-mutant lung cancer

项目摘要 奥希替尼是一种第三代EGFR酪氨酸激酶抑制剂（TKI），是目前一线 EGFR突变型肺癌患者的治疗。虽然奥希替尼在诱导肿瘤消退方面是有效的， 改善生活质量和延长大多数患者的生存期，但它不是治愈性的。早期的后天性研究 耐药性表明，即使在对耐药机制进行标准的组织学和基因组评估后， 奥希替尼耐药性的大部分仍然未被表征。这种不完整的理解 奥希替尼耐药性对开发用于临床应用的新的和有效的疗法构成了重大障碍。我们 假设，与早期的EGFR抑制剂相比，非基因组机制正在驱动EGFR抑制剂， 大多数对一线奥希替尼获得性耐药。迄今为止，EGFR TKI获得性耐药的评估 机制集中在基因组抗性突变，扩增和融合，部分原因是这些 可以在肿瘤组织或基于血液的ctDNA液体活检中容易地检测到。在这个项目中，我们力求 发现非基因组奥希替尼耐药谱。我们的主要目标是确定肿瘤的内在 奥希替尼耐药机制以及肿瘤外源性微环境耐药机制。在 目的1，我们将使用RARE-Seq，一种新的基于血液的测定来定量肿瘤基因表达模式， EGFR突变型NSCLC患者对奥希替尼的耐药性。在目标2中，我们将研究肿瘤细胞 奥希替尼耐药的外在机制，利用我们强大的翻译基础设施， 来自奥希替尼耐药活检的癌症相关成纤维细胞模型。我们将用这些模型来解剖 CAFs，肿瘤细胞和免疫细胞之间的功能相互作用，我们将整合这些结果与 临床活检的空间分子分析。总的来说，本提案中所述的研究将产生一个 全面了解奥希替尼耐药性，为未来开发治疗奠定基础， 克服对奥希替尼的耐药性。

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.