"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。”

• 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
• 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

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.

摘要 头颈部鳞状细胞癌（HNSCC）是第六常见的癌症，但治疗 HNSCC仍然有限。目前HNSCC的治疗通常涉及手术和放化疗， 最新单药治疗或与西妥昔单抗、EGFR靶向单克隆抗体或免疫检查点联合治疗 抑制剂的这些方案通常与并发症，如颌骨僵硬，吞咽困难，吞咽 和语言障碍，以及HNSCC通常对现有治疗难以治愈。 染色体拷贝数变异（即，染色体区域的获得或丢失）是最常见的遗传 HNSCC中的改变;最普遍的一种是“3q扩增子”，即，远端节段的扩增 3号染色体为了确定HNSCC干预的替代靶点，我们扫描了蛋白激酶 在“3Q放大器”中。我们最近定义了扩增的TNIK，一种丝氨酸/苏氨酸蛋白激酶， “3q扩增子”作为肺鳞状细胞癌（LSCC）的有希望的靶点。我们发现TNIK抑制 抑制LSCC患者来源的异种移植物的生长。一致地，在具有TNIK的HNSCC细胞系中， 扩增，抑制TNIK降低HNSCC细胞活力。TNIK促进LSCC细胞活力的机制 通过激活粘着斑激酶（FAK）和雅普和TAZ（雅普/TAZ）转录因子。FAK和 雅普/TAZ在HNSCC中经常异常激活，并且已知这两种途径有助于HNSCC的形成。 多种肿瘤类型中的HNSCC进展和治疗抗性。鉴于TNIK在20%的 HNSCC及其下游效应物被激活，我们提出了一个模型，其中扩增的TNIK是一种致癌因子。 激活负责控制细胞活力和促进治疗的基本信号传导途径的驱动因子 HNSCC中的耐药性。为了检验这个模型，我们提出了两个具体目标。在目标1中，我们将测试TNIK是否 通过激活FAK和雅普/TAZ维持HNSCC细胞增殖和活力。在目标2中，我们将研究 抑制TNIK是否以及如何使HNSCC细胞对化疗和EGFR靶向单克隆抗体敏感 HNSCC细胞中的抗体。我们将通过结合使用基于细胞的增殖和 存活测定，结合靶向TNIK、FAK和雅普/TAZ的药理学和遗传学方法。 这些研究将确定HNSCC进展和耐药性的新机制。这项建议会 使我们能够为竞争性R 01应用产生新的假设，以研究靶向的后果 TNIK在HNSCC临床前模型中的应用符合我们确定新治疗靶点的长期目标 用于HNSCC的干预。