"Role of Amplified Protein Kinases in Head and Neck Squamous Cell Carcinoma Progression and Therapy Resistance."

“扩增的蛋白激酶在头颈鳞状细胞癌进展和治疗耐药中的作用。”

基本信息

批准号：
10725901
负责人：
Pedro Torres-Ayuso
金额：
$ 31.7万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
2023-08-15 至 2025-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725901
关键词：
3q26 Bioinformatics Biological Assay Cell Line Cell Proliferation Cell Survival Cells Cetuximab Chemoresistance Chromosome 3 Chromosomes Clinical Colorectal Cancer Copy Number Polymorphism Coupled Data Deglutition Deglutition Disorders Distal Epidermal Growth Factor Receptor Focal Adhesion Kinase 1 Foundations Genetic Transcription Goals Grant Growth Head and Neck Squamous Cell Carcinoma Immune checkpoint inhibitor Impairment Intervention Jaw MAP4K4 gene Malignant Neoplasms Measures Mediating Modeling Monoclonal Antibodies Mutation National Institute of Dental and Craniofacial Research Oncogenes Oncogenic Operative Surgical Procedures PIK3CA gene Pathway interactions Patients Pre-Clinical Model Proliferating Protein Kinase Protein-Serine-Threonine Kinases Publishing Refractory Research Personnel Resistance Role Scanning Signal Pathway Signal Transduction Speech Squamous Cell Lung Carcinoma Squamous cell carcinoma Supporting Cell TRAF2 gene Testing Therapeutic Toxic effect Work cancer type carcinogenesis cell growth chemoradiation chemotherapy chromosome loss comorbidity expectation extracellular falls genetic approach improved inhibitor kinase inhibitor mutant new therapeutic target overexpression patient derived xenograft model pharmacologic programs small hairpin RNA small molecule inhibitor targeted treatment therapy resistant transcription factor treatment and outcome tumor tumor growth

项目摘要

ABSTRACT Head and neck squamous cell carcinomas (HNSCC) are the sixth most frequent cancer, but treatments for HNSCC are still limited. Current management of HNSCC often involves surgery and chemo-radiotherapy, the latest alone or combined with cetuximab, an EGFR-targeting monoclonal antibody, or immune checkpoint inhibitors. These regimes usually concur with comorbidities such as jaw stiffness, dysphagia, and swallowing and speech impairments, and HNSCC are often refractory to existing treatments. Chromosome copy number variations (i.e., gain or loss of chromosome regions) are the most common genetic alterations in HNSCC; one of the most prevalent is the `3q amplicon', i.e., the amplification of the distal segment of chromosome 3. To identify alternative targets for intervention in HNSCC, we have scanned for protein kinases within the `3q amplicon'. We recently defined amplified TNIK, a serine/threonine protein kinase encoded within the `3q amplicon', as a promising target in lung squamous cell carcinoma (LSCC). We found that TNIK inhibition suppressed the growth of LSCC patient-derived xenografts. Consistently, in HNSCC cell lines with TNIK amplification, inhibiting TNIK reduced HNSCC cell viability. Mechanistically, TNIK promotes LSCC cell viability by activating the focal adhesion kinase (FAK) and the YAP and TAZ (YAP/TAZ) transcription factors. FAK and YAP/TAZ are frequently aberrantly activated in HNSCC, and these two pathways are known to contribute to HNSCC progression and therapy resistance in multiple tumor types. Given that TNIK is amplified in 20% of HNSCC and its downstream effectors activated, we propose a model in which amplified TNIK is an oncogenic driver that activates essential signaling pathways responsible for controlling cell viability and promoting therapy resistance in HNSCC. To test this model, we propose two Specific Aims. In Aim 1, we will test whether TNIK sustains HNSCC cell proliferation and viability by activating FAK and YAP/TAZ. In Aim 2, we will investigate whether and how inhibiting TNIK sensitizes HNSCC cells to chemotherapy and EGFR-targeting monoclonal antibodies in HNSCC cells. We will test these two aims by using a combination of cell-based proliferation and survival assays, coupled with pharmacological and genetic approaches to target TNIK, FAK, and YAP/TAZ. These studies will identify new mechanisms of HNSCC progression and chemoresistance. This proposal will enable us to generate new hypotheses for a competitive R01 application to study the consequences of targeting TNIK in preclinical models of HNSCC in alignment with our long-term goal of identifying new therapeutic targets for intervention in HNSCC.

抽象的头颈部鳞状细胞癌（HNSCC）是第六大癌症，但治疗 HNSCC仍然有限。 HNSCC的当前管理通常涉及手术和化学疗法，最新单独或与Cetuximab，EGFR靶向单克隆抗体或免疫检查点结合抑制剂。这些制度通常与合并症，例如下颌僵硬，吞咽困难和吞咽语音障碍和HNSCC通常对现有治疗措施难治。染色体拷贝数变化（即染色体区域的增益或损失）是最常见的遗传 HNSCC的改变；最普遍的之一是“ 3Q扩增子”，即远端段的扩增染色体3。为了识别HNSCC干预的替代靶标，我们已经扫描了蛋白激酶在“ 3Q Amplicon”中。我们最近定义了Amplified Tnik，这是一种编码的丝氨酸/苏氨酸蛋白激酶 “ 3Q Amplicon”，是肺鳞状细胞癌（LSCC）中有希望的靶标。我们发现TNIK抑制作用抑制了LSCC患者衍生的异种移植物的生长。一贯，在HNSCC细胞系中，带有TNIK 扩增，抑制TNIK降低了HNSCC细胞活力。从机械上讲，TNIK促进LSCC细胞活力通过激活焦点粘附激酶（FAK）以及YAP和TAZ（YAP/TAZ）转录因子。 fak和 YAP/TAZ在HNSCC中经常被异常激活，这两种途径已知有助于多种肿瘤类型中的HNSCC进展和耐药性。鉴于TNIK在20％的20％中被放大 HNSCC及其下游效应子已激活，我们提出了一个模型，其中放大TNIK是一种致癌的模型激活负责控制细胞活力和促进治疗的基本信号通路的驱动器 HNSCC的阻力。为了测试该模型，我们提出了两个具体目标。在AIM 1中，我们将测试是否tnik 通过激活FAK和YAP/TAZ来维持HNSCC细胞增殖和生存能力。在AIM 2中，我们将调查 TNIK是否以及如何抑制HNSCC细胞对化学疗法和EGFR靶向单克隆 HNSCC细胞中的抗体。我们将通过结合基于细胞的增殖和生存测定，再加上针对TNIK，FAK和YAP/TAZ的药理和遗传方法。这些研究将确定HNSCC进展和化学抗性的新机制。该提议将使我们能够为竞争性R01应用生成新的假设，以研究目标的后果在HNSCC的临床前模型中，TNIK与我们确定新的治疗目标的长期目标保持一致用于干预HNSCC。