Clinical specimen tumor-TME acquired resistance

项目摘要/摘要：BAATAAR-UP中此翻译项目的目标是描述 非小细胞肺对分子治疗获得性耐药的机制及治疗对策 肿瘤-肿瘤微环境(TME)生态系统及其可塑性 治疗。获得性耐药(AR)被定义为在积极治疗期间和之后发生的肿瘤进展 最初的治疗反应。最重要的假设是，AR可以在治疗上被 定义允许肿瘤在治疗期间存活和生长的细胞和信号网络。对.的使用 抑制癌基因驱动因素改变的分子靶向治疗，如突变的EGFR和KRAS和 阻断免疫抑制检查点，如PD1/L1，正在改善侵袭性疾病患者的预后 肿瘤，包括非小细胞肺癌，它仍然是癌症死亡的主要原因。尽管影响深远 进展，将非小细胞肺癌转变为慢性或可治愈癌症的一个主要挑战是AR，它使致命的 患者的肿瘤进展情况。了解推动AR的机制对于制定战略至关重要 中和它，并诱导持续的抗肿瘤反应，以提高患者的存活率。关键的知识差距是 肿瘤细胞/TME细胞相互作用和空间关系是否以及如何促进AR。的另一个方面 AR的演变不明确是典型的不完全反应和残留疾病的基础 在治疗期间。这种残留的疾病包含耐药癌细胞和相互作用的TME细胞 共同推动向AR的积极过渡。定义这种转变是如何发生的可以提供战略 去阻挠它。我们在之前的U54资助期完成的工作表明，癌基因驱动的非小细胞肺癌 包含丰富的细胞生态系统，在分子处理过程中进化(例如，EGFR、ALK和RAS途径 目标代理)。我们在肿瘤细胞和TME细胞中发现了异质性和可塑性，包括免疫 和非免疫细胞类型，以及不同临床治疗状态下的空间关系，包括在AR，我们 假设对应收账款有集体贡献。其中包括肿瘤巨噬细胞之间的双向相互作用。 以及癌细胞、肿瘤成纤维细胞和癌细胞通过离散的信号电路促进癌细胞 存活，并在AR时将TME重塑为更亲肿瘤的表型。例子包括细胞因子(CSF1，TNFa， 、肿瘤巨噬细胞与癌细胞间的CD47信号转导及巨噬细胞迁移抑制 肿瘤成纤维细胞与肿瘤之间的MIF-CD74/CD44和细胞外基质(ECM)/整合素信号转导 AR处的细胞。我们的目标是定义和治疗这些癌细胞和TME细胞。 治疗上阻挠AR的网络。我们专注于临床上重要的和流行的非小细胞肺癌亚型 通过致癌突变体EGFR和KRAS以及目前临床靶向抑制这些主要致癌物质 司机。提出了两个具体目标。我们的工作将突出推动AR跨越肿瘤的机制-TME 在EGFR和KRAS驱动的非小细胞肺癌中持续存在，并确定翻译的对抗治疗策略。

Project Summary/Abstract: The goal of this translational Project within BAATAAR-UP is to characterize the mechanisms of, and therapeutically counteract, acquired resistance to molecular therapies in non-small cell lung cancer (NSCLC) by delineating the tumor-tumor microenvironment (TME) ecosystem and its plasticity during treatment. Acquired resistance (AR) is defined as tumor progression that occurs during active therapy and after an initial therapy response. The overarching hypothesis is that AR can be therapeutically counteracted by defining the cellular and signaling networks allowing tumors to survive and grow during therapy. The use of molecularly targeted therapies that inhibit oncogenic driver alterations such as mutant EGFR and KRAS and block immunosuppressive checkpoints such as PD1/L1 is improving outcomes for patients with aggressive tumors including NSCLC, which nonetheless remains the leading cause of cancer mortality. Despite profound progress, a major challenge to transforming NSCLC into a chronic or curable cancer is AR that enables lethal tumor progression in patients. Understanding the mechanisms driving AR is essential to develop strategies to counteract it and induce sustained anti-tumor responses to improve patient survival. Critical knowledge gaps are whether and how tumor cell/TME cell interactions and spatial relationships promote AR. Another aspect of the evolution of AR that is poorly defined is the basis of the incomplete response and residual disease that is typical during therapy. This residual disease contains drug tolerant cancer cells and interactive TME cells that evolve together to promote the aggressive transition into AR. Defining how this transition occurs could provide strategies to thwart it. Our work accomplished during the prior U54 funding period showed that oncogene-driven NSCLCs contain a rich cellular ecosystem that evolves during molecular treatments (e.g., EGFR, ALK, and RAS pathway targeted agents). We discovered heterogeneity and plasticity in tumor cells and TME cells, including immune and non-immune cell types, and spatial relationships at different clinical treatment states including at AR that we hypothesize contribute collectively to AR. These include bi-directional interactions between tumor macrophages and cancer cells and tumor fibroblasts and cancer cells via discrete signaling circuits that promote cancer cell survival and remodel the TME into a more pro-tumor phenotype at AR. Examples include cytokine (CSF1, TNFa, IL1b), and CD47 signaling between tumor macrophages and cancer cells and macrophage migration inhibitory factor (MIF)-CD74/CD44 and extracellular matrix (ECM)/integrin signaling between tumor fibroblasts and cancer cells at AR. Our goal is to define and therapeutically target these, and additional, cancer cell and TME cell networks to therapeutically thwart AR. We focus on clinically important and prevalent NSCLC subtypes defined by oncogenic mutant EGFR and KRAS and current clinical targeted inhibitors against these major oncogenic drivers. Two Specific Aims are proposed. Our work will highlight mechanisms driving AR across the tumor-TME continuum in EGFR- and KRAS-driven NSCLCs and identify counteracting therapeutic strategies for translation.