Molecular control of tumor-initiating cells in Ras-driven cancers

Ras 驱动的癌症中肿瘤起始细胞的分子控制

基本信息

批准号：
10752472
负责人：
Heidi Vieira
金额：
$ 3.77万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752472
关键词：
Affect Aftercare Anchorage-Independent Growth Binding Biological Assay CRISPR/Cas technology Cancer Patient Cancer cell line Cell physiology Cells Characteristics Clinical Clustered Regularly Interspaced Short Palindromic Repeats Colorectal Cancer Colorectal Neoplasms Data Dependence Development Drug Efflux Drug resistance Engineering Frequencies Goals Impairment In Vitro KSR gene Knock-out Lung Neoplasms MEK inhibition MEKs Maintenance Malignant Neoplasms Mediating Metabolic Modality Modeling Molecular Mus Mutate Mutation Natural regeneration Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal Cell Oncogenic Organoids Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Population Pre-Clinical Model Process Property Protac RAS driven cancer RAS driven tumor RSU1 gene Recurrence Recurrent tumor Regulation Research Resistance Resistance development Role Signal Pathway Signal Transduction Solid Neoplasm System Testing Therapeutic Therapeutic Index Transgenes Tumor Cell Line Tumor Expansion Tumor Promotion cancer cell cell growth clinical efficacy combat in vivo inhibitor lung cancer cell mortality mutant neoplastic cell novel novel therapeutic intervention pre-clinical prevent protein degradation scaffold self-renewal stemness targeted treatment therapeutic target tumor tumor ablation tumor initiation tumorigenic

项目摘要

Project Summary Tumor Initiating Cells (TICs) are a subpopulation of tumor cells defined by their ability to self-renew and regenerate the heterogeneous tumor. TICs have altered metabolic and drug efflux properties, allowing them to persist as a sanctuary population of resistant cells during treatment. As such, TICs mediate tumor recurrence and metastasis, which are key contributors to mortality. To date, however, there are no therapies targeting the TIC population in solid tumors. My data show that the formation and maintenance of TICs in Ras-driven colorectal and lung tumor cell lines are critically dependent on the molecular scaffold Kinase Suppressor of Ras 1 (KSR1). KSR1 coordinates signaling through the Raf-MEK-ERK cascade downstream of oncogenic Ras. KSR1 is necessary for Ras-driven tumor formation, but dispensable for normal cell growth. Moreover, ksr1-/- mice are phenotypically normal but resistant to cancer formation. These characteristics highlight the value of KSR1 as a potential therapeutic target. Our data further show that KSR1 KO can prevent MEK inhibitor trametinib-mediated expansion of the TIC population and restore sensitivity to trametinib in both NSCLC and in CRC where resistance currently limits clinical utility of this drug. Further characterization using KSR1 transgenes with defined mutations in downstream effector-binding regions has identified KSR1 interaction with both ERK and AMPK to be implicated in maintenance of the TIC population, in vitro clonogenicity, and resistance to trametinib. These data suggest the hypothesis that KSR1-dependent ERK and AMPK activation in Ras-driven cancers plays a selective role in the formation of tumor-initiating cells and the drug resistance conveyed by this subpopulation. I will test this hypothesis by 1) defining the proximal KSR1-dependent signaling pathways that control TICs and trametinib resistance; and 2) assessing the ability of targeted KSR1 degradation to impair tumor-initiating capacity in a preclinical tumor organoid model. Completion of these aims will expand mechanistic understanding of Ras-driven TIC formation and maintenance and may reveal a novel therapeutic approach to treat TIC-mediated resistance, recurrence, and metastasis.

项目摘要肿瘤引发细胞（TICS）是肿瘤细胞的亚群，其自我更新能力和再生异质性肿瘤。抽动改变了代谢和药物外的特性，使它们能够在治疗过程中，持续存在抗性细胞的庇护所。因此，抽动介导肿瘤复发和转移，这是死亡率的关键因素。但是，迄今为止，还没有针对的疗法实体瘤中的抽动种群。我的数据表明，RAS驱动的抽动的形成和维护结直肠癌和肺肿瘤细胞系关键取决于分子支架激酶激酶抑制剂 RAS 1（KSR1）。 KSR1通过致癌Ras下游的RAF-Mek-ERK级联反应进行信号传导。 KSR1对于RAS驱动的肿瘤形成是必需的，但对于正常细胞生长来说是必不可少的。此外，KSR1 - / - 小鼠在表型上是正常的，但对癌症的形成有抵抗力。这些特征突出了 KSR1作为潜在的治疗靶标。我们的数据进一步表明KSR1 KO可以防止MEK抑制剂 TIC种群的Trametinib介导的扩展，并恢复NSCLC和IN中对Trametinib的敏感性 CRC当前阻力限制了该药物的临床实用性。使用KSR1进一步表征在下游效应器结合区域中具有明确突变的转基因已经确定了KSR1的相互作用 ERK和AMPK都与维持TIC种群，体外克隆性和对曲米替尼的抗性。这些数据表明假设KSR1依赖性ERK和AMPK激活在RAS驱动的癌症中，癌症在肿瘤发射细胞的形成和耐药性中起选择性作用通过这个亚种群传达。我将通过1）定义近端KSR1依赖性测试该假设控制抽动和曲米替尼的信号通路； 2）评估目标KSR1的能力降解以损害临床前肿瘤器官模型中肿瘤发射能力。这些目标的完成将扩大对RAS驱动的TIC形成和维护的机械理解，并可能揭示出新颖的治疗TIC介导的抗性，复发和转移的治疗方法。