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。肺癌是世界范围内癌症死亡率的主要原因，非小细胞肺癌（NSCLC） 肺癌（NSCLC）是肺癌的主要组织学亚型，肺腺癌是主要亚型 的NSCLC。尽管使用靶向治疗取得了临床进展，但耐药性仍然是一个问题， 限制了患者的生存。耐药性进化的一个不太清楚的方面是耐药性， “持久”细胞状态，其中癌细胞亚群在初始靶向治疗中存活，以形成最小的细胞毒性。 残留病（MRD）储库是获得性耐药性的前兆。我们提出了一个创新的， 多学科合作项目，希望通过定义 Hippo-YAP通路在促进药物耐受性和靶向电流通路的MRD中的作用 治疗在R 01第一个融资周期完成的工作基础上， 发现Hippo-YAP信号通路作为许多疾病中的关键分子回路和治疗靶点， 由RTK-RAS-MAPK信号转导过度激活驱动的癌症。我们的数据表明， 其中雅普激活是RTK-RAS-MAPK靶向过程中耐药状态的关键功能特征 抑制NSCLC。我们观察到雅普在多癌基因驱动的NSCLC临床前治疗过程中的激活， 用EGFR、ALK、KRAS和SHP 2抑制剂治疗的模型。雅普上调可促进 几种生存因子，包括BCL-xL和RTK，如FGFR 1和ErbB 2。此外，通过单- 在从接受治疗的患者获得的临床标本中纵向进行细胞RNA测序（scRNAseq） 使用靶向抑制剂，我们发现残留的癌细胞通常表现出谱系可塑性和向 一种肺泡型（AT）1/2样转录状态，是慢循环、耐药癌症的新表型 细胞我们证实这发生在真正的癌细胞中（即，不是来自错误注释的正常肺泡细胞）， 与未经治疗的腺癌或正常AT 1/2细胞不同。我们的数据表明雅普在以下方面的作用： 促进药物耐受性和这种新形式的谱系可塑性。用雅普/TEAD抑制雅普信号传导 临床开发中的小分子抑制剂抑制耐药癌细胞存活， AT 1/2样谱系转换的分子标记物的表达。我们建议进一步检验假设， 雅普信号通路是调控RTK-MAPK通路生物学和临床反应的关键分子开关 抑制剂的在目的1中，我们明确了雅普在促进药物耐受和AT 1/2样谱系可塑性中的作用 存在于RTK-RAS-MAPK驱动的NSCLC中的药物耐受性癌细胞中。我们还测试了药理学是否 在临床前模型中，抑制雅普/TEAD可阻碍MRD并增强对RTK-RAS抑制剂反应。在 目的2：研究雅普/TEAD激活和AT 1/2样谱系转换的分子特征， 使用治疗前和治疗中患者肿瘤的MRD和临床结局。该项目提供了深入了解 雅普和谱系可塑性在治疗耐受性和MRD中的作用，具有未来临床转化的潜力。