Characterization of YAP as a rational companion target in lung cancer

YAP 作为肺癌合理伴随靶点的特征

• 批准号: 10365912
• 负责人: Trever G Bivona
• 金额: $ 38.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365912
• 关键词: Adenocarcinoma; Alveolar; Alveolar Cell; Applications Grants; BCL2L1 gene; Biological; Biological Markers; Cancer Etiology; Cancer Patient; Cell Survival; Cells; Clinical; Clinical Trials; Companions; Data; Disease Outcome; Disease Reservoirs; Drug Tolerance; Drug resistance; ERBB2 gene; Epidermal Growth Factor Receptor; Evolution; FGFR1 gene; Funding; Future; Gene Expression Profile; Genetic Transcription; Goals; Growth; Histologic; In Vitro; KRAS2 gene; Link; Lung Adenocarcinoma; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Non-Small-Cell Lung Carcinoma; Nuclear; Oncogenes; Oncogenic; Oncoproteins; Outcome; Output; PTPN11 gene; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Pre-Clinical Model; Proteins; Ras Inhibitor; Regimen; Residual Cancers; Residual Neoplasm; Resistance; Role; Safety; Sampling; Signal Pathway; Signal Transduction; Specimen; Switch Genes; System; Testing; Therapeutic Clinical Trial; Up-Regulation; Work; cancer cell; cell type; clinical development; clinical translation; clinically relevant; cohort; improved; inhibitor; innovation; insight; molecular marker; mortality; multidisciplinary; mutant; neoplastic cell; novel; precision medicine; primitive cell; response; single-cell RNA sequencing; small molecule; small molecule inhibitor; success; survival outcome; targeted treatment; therapeutic target; therapy resistant; tumor

PROJECT ABSTRACT. Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) the predominant histologic subtype of lung cancer and lung adenocarcinoma the major subset of NSCLC. Despite clinical progress with the use of targeted therapies, drug resistance remains a problem that limits patient survival. A less well understood aspect of the evolution of drug resistance is the drug tolerant, “persister” cell state, in which a subpopulation of cancer cells survives initial targeted treatment to form a minimal residual disease (MRD) reservoir that is a precursor to acquired resistance. We propose an innovative, multidisciplinary and collaborative project to hopefully improve the survival of NSCLC patients by defining the role that the Hippo-YAP pathway plays in promoting drug tolerance and MRD to current pathway targeted therapies. Extending work that we completed in the first funding cycle of this R01, we aim to capitalize on our discovery of the Hippo-YAP signaling pathway as a critical molecular circuit and therapeutic target in the many cancers driven by hyperactivation of RTK-RAS-MAPK signaling. Our data suggest an emerging paradigm in which YAP activation is a key functional feature of the drug tolerant state during RTK-RAS-MAPK targeted inhibition in NSCLC. We observed YAP activation during therapy in multiple oncogene-driven NSCLC preclinical models treated with EGFR, ALK, KRAS and SHP2 inhibitors. YAP upregulation promoted the expression of several survival factors including BCL-xL and RTKs such as FGFR1 and ErbB2. Furthermore, through single- cell RNA sequencing (scRNAseq) performed longitudinally in clinical specimens obtained from patients treated with targeted inhibitors, we discovered that residual cancer cells often show lineage plasticity and a transition to an alveolar type (AT)1/2-like transcriptional state that is a novel phenotype of slow cycling, drug tolerant cancer cells. We verified this occurred in bona fide cancer cells (i.e., not from misannotated normal alveolar cells) and was distinct from therapy-naïve adenocarcinoma or normal AT1/2 cells. Our data suggest a role for YAP in promoting drug tolerance and this novel form of lineage plasticity. Inhibition of YAP signaling with YAP/TEAD small molecule inhibitors that are in clinical development suppressed drug tolerant cancer cell survival and expression of molecular markers of the AT1/2-like lineage switch. We propose to further test the hypothesis that YAP signaling is a key molecular switch that regulates the biological and clinical response to RTK-MAPK pathway inhibitors. In Aim 1, we define the role of YAP in promoting drug tolerance and the AT1/2-like lineage plasticity present in drug tolerant cancer cells in RTK-RAS-MAPK-driven NSCLCs. We also test whether pharmacologic inhibition of YAP/TEAD can thwart MRD and enhance response to RTK-RAS inhibitors in preclinical models. In Aim 2, we study molecular features of YAP/TEAD activation and the AT1/2-like lineage switch as biomarkers of MRD and clinical outcomes using tumors from patients before and on treatment. This project offers insight into the role of YAP and lineage plasticity in therapy tolerance and MRD, with potential for future clinical translation.

项目摘要。肺癌是全球癌症死亡率的主要原因，非小细胞肺 癌症（NSCLC）肺癌和肺腺癌的主要组织学亚型主要子集 NSCLC。尽管使用有针对性疗法，但耐药性仍然是一个问题 限制患者的生存。耐药性进化的一个不太了解的方面是耐药物， “毅力”细胞状态，其中癌细胞的亚群生存着初始靶向治疗，形成最小 残留疾病（MRD）储层是获得性抗性的先驱。我们提出了一个创新的 多学科和协作项目，希望通过定义NSCLC患者的生存 Hippo-YAP途径在促进药物耐受性和MRD到靶向的当前途径中所发挥的作用 疗法。扩展我们在此R01的第一个融资周期中完成的工作，我们的目标是利用我们的 在许多人中发现河马-YAP信号通路是关键分子电路和治疗靶标的 由RTK-RAS-MAPK信号传导过度激活驱动的癌症。我们的数据表明在 在RTK-RAS-MAPK目标期间，哪种YAP激活是药物耐受状态的关键功能特征 NSCLC的抑制作用。我们观察到在多种致癌基因驱动的NSCLC临床前的治疗过程中YAP激活 用EGFR，ALK，KRAS和SHP2抑制剂处理的模型。 yap上调促进了 几种生存因子，包括BCl-XL和RTK，例如FGFR1和ERBB2。此外，通过 细胞RNA测序（SCRNASEQ）在从接受治疗的患者获得的临床样本中进行纵向进行 使用靶向抑制剂，我们发现残留的癌细胞经常显示谱系可塑性，并过渡到 大型循环，药物耐受癌的新表型（AT）1/2样转录状态（AT）。 细胞。我们验证了这种情况发生在真正的癌细胞（即不来自正常肺泡细胞）和 我们与未接受治疗的腺癌或正常AT1/2细胞不同。我们的数据表明YAP在 促进药物耐受性和这种新型的谱系可塑性。用yap/tead抑制yap信号传导 临床发育中的小分子抑制剂抑制了药物耐受性癌细胞的存活和 AT1/2样谱系开关的分子标记的表达。我们建议进一步检验以下假设 YAP信号传导是一个关键的分子开关，可调节对RTK-MAPK途径的生物学和临床反应 在AIM 1中，我们定义了YAP在促进药物耐受性和AT1/2样谱系可塑性中的作用 在RTK-RAS-MAPK驱动的NSCLC中存在于药物耐受性癌细胞中。我们还测试了药理学是否 抑制YAP/TEAD可以阻止MRD并增强对临床前模型中RTK-RAS抑制剂的反应。 AIM 2，我们研究YAP/TEAD激活的分子特征和AT1/2样谱系开关作为生物标志物 MRD和临床结局在治疗前后使用患者的肿瘤。该项目提供了有关 YAP和谱系可塑性在治疗耐受性和MRD中的作用，并有可能进行未来的临床翻译。