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

"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
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-15 至 2025-08-14

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中文摘要
翻译
摘要 头颈部鳞状细胞癌(HNSCC)是第六大常见癌症,但治疗 HNSCC仍然是有限的。目前HNSCC的治疗通常涉及手术和化疗-放射治疗, 最新单独或与西妥昔单抗联合使用,西妥昔单抗是一种针对EGFR的单抗或免疫检查点 抑制剂。这些症状通常伴随有颌骨僵硬、吞咽困难和吞咽等合并症。 和语言障碍,以及HNSCC通常对现有的治疗方法难以奏效。 染色体拷贝数变异(即染色体区域的增加或丢失)是最常见的遗传 HNSCC的改变;最常见的是‘3q扩增’,即远端片段的扩增 为了确定干预HNSCC的替代靶点,我们扫描了蛋白激酶 在‘3q扩增器’内。我们最近定义了扩增的tnik,这是一种编码在 作为肺鳞状细胞癌(LSCC)靶点的“3q”扩增。我们发现tnik抑制 抑制喉鳞状细胞癌患者来源的异种移植的生长。一致地,在带有tnik的HNSCC细胞系中 扩增、抑制tnik使HNSCC细胞活力降低。机制上,tnik促进喉鳞状细胞癌细胞活性 通过激活粘着斑激酶(FAK)以及YAP和TAZ(YAP/TAZ)转录因子。FAK和 YAP/TAZ在HNSCC中经常异常激活,这两条途径被认为有助于 多种肿瘤类型中的HNSCC进展和治疗耐药。鉴于tnik在20%的人中被放大 HNSCC及其下游效应分子被激活,我们提出了一个模型,在该模型中扩增的tnik是致癌的 驱动程序,激活负责控制细胞活性和促进治疗的基本信号通路 HNSCC中的耐药性。为了测试该模型,我们提出了两个具体目标。在目标1中,我们将测试tnik 通过激活FAK和YAP/TAZ维持HNSCC细胞的增殖和存活。在目标2中,我们将调查 抑制tnik是否以及如何增加HNSCC细胞对化疗和EGFR靶向的单抗的敏感性 HNSCC细胞中的抗体。我们将使用基于细胞的增殖和组合来测试这两个目标 生存分析,结合针对tnik、FAK和YAP/TAZ的药理学和遗传学方法。 这些研究将确定HNSCC进展和化疗耐药的新机制。这项提议将 使我们能够为竞争性的R01应用程序生成新的假设,以研究目标确定的结果 TNICK在HNSCC的临床前模型中的应用与我们寻找新治疗靶点的长期目标保持一致 对HNSCC的干预。
英文摘要
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.
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