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

• 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
• 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

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.

项目概要 肿瘤起始细胞 (TIC) 是肿瘤细胞的一个亚群，其定义为具有自我更新和自我更新能力。 再生异质肿瘤。 TIC 改变了代谢和药物流出特性，使它们能够 在治疗期间作为耐药细胞的庇护所持续存在。因此，TIC 介导肿瘤复发 和转移，这是死亡率的关键因素。但迄今为止，尚无针对该疾病的治疗方法 实体瘤中的 TIC 群体。我的数据显示 TIC 的形成和维持是 Ras 驱动的 结直肠和肺肿瘤细胞系严重依赖于分子支架激酶抑制剂 拉斯 1 (KSR1)。 KSR1 通过致癌 Ras 下游的 Raf-MEK-ERK 级联协调信号传导。 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可有可无的。此外，ksr1-/- 小鼠表型正常，但能抵抗癌症形成。这些特点凸显了其价值 KSR1作为潜在的治疗靶点。我们的数据进一步表明KSR1 KO可以阻止MEK抑制剂 曲美替尼介导的 TIC 群体扩张并恢复 NSCLC 和非小细胞肺癌中对曲美替尼的敏感性 结直肠癌的耐药性目前限制了该药物的临床应用。使用 KSR1 进一步表征 在下游效应子结合区具有明确突变的转基因已鉴定出 KSR1 与 ERK 和 AMPK 均与 TIC 群体的维持、体外克隆性和 对曲美替尼耐药。这些数据表明 KSR1 依赖性 ERK 和 AMPK 激活的假设 在 Ras 驱动的癌症中，它在肿瘤起始细胞的形成和耐药性中发挥选择性作用 由该亚群传达。我将通过 1) 定义近端 KSR1 依赖性来检验这个假设 控制 TIC 和曲美替尼耐药性的信号通路； 2) 评估目标 KSR1 的能力 降解以损害临床前肿瘤类器官模型中的肿瘤启动能力。完成这些目标 将扩大对 Ras 驱动的 TIC 形成和维持的机制理解，并可能揭示一种新的 治疗 TIC 介导的耐药、复发和转移的治疗方法。