Project 4: Role of Receptor Tyrosine Kinase AXL in HNSCC Therapy Resistance

项目 4：受体酪氨酸激酶 AXL 在 HNSCC 治疗耐药中的作用

• 批准号: 9768204
• 负责人: DERIC L WHEELER
• 金额: $ 24.98万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9768204
• 关键词: Ablation; Antibodies; Apoptosis; Biological Markers; Biological Models; Biopsy; CRISPR/Cas technology; Caspase; Cell Line; Cessation of life; Cetuximab; Clinic; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Cyclophosphamide; Data; Diagnosis; Diagnostic; Distant Metastasis; Down-Regulation; ERBB3 gene; Epidermal Growth Factor Receptor; Future; Genetic; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; In Vitro; Investigation; Knowledge; Laboratories; Malignant Neoplasms; Mediating; Metastatic/Recurrent; Modeling; Molecular; Molecular Target; Monoclonal Antibodies; Mutation Analysis; Neoplasm Metastasis; Newly Diagnosed; Operative Surgical Procedures; PI3K/AKT; Pathogenesis; Pathologic; Pathologist; Pathway interactions; Patients; Phosphotransferases; Play; Proliferation Marker; Proteomics; Radiation; Refractory; Relapse; Resected; Resistance; Role; S-Phase Fraction; Scientist; Series; Signal Transduction; Specimen; Survival Rate; Testing; Therapeutic; Translating; Translations; Treatment outcome; United States; Universities; Wisconsin; Xenograft procedure; axl receptor tyrosine kinase; base; cancer therapy; chemotherapy; cohort; experience; experimental study; improved; in vivo; in vivo Model; innovation; insight; mouse model; novel; novel therapeutics; overexpression; predictive marker; primary endpoint; resistance mechanism; response; secondary endpoint; small hairpin RNA; small molecule inhibitor; src-Family Kinases; targeted agent; therapeutic target; therapy resistant; translational physician; tumor; tumor growth; virtual

PROJECT SUMMARY The primary objective of this proposal is to examine the receptor tyrosine kinase AXL as a driver of cetuximab resistance in Head and Neck Cancer (HNC). Cetuximab, a monoclonal antibody targeting the EGFR, is the only approved molecular targeting agent in the management of HNC. Despite well established benefit, the majority of patients do not respond to cetuximab, and those who do respond ultimately manifest resistance. Intrinsic and acquired resistance to cetuximab is a major obstacle to improving treatment outcome in HNSCC. Further, limited molecular understanding of cetuximab resistance mechanisms reveals a gap in knowledge in HNC therapy. To identify novel, targetable mechanisms of cetuximab resistance in HNC we employ human tumors, patient-derived xenografts (PDXs), and several models of intrinsic and acquired resistance. We have identified that 1) AXL is overexpressed in HNC and is significantly associated with higher pathologic grade, metastases, and shorter survival, 2) PDXs resistant to cetuximab have high AXL expression compared to cetuximab-sensitive PDXs, and AXL blockade can re-sensitize resistant tumors, 3) overexpression of AXL in cetuximab-sensitive HNC lines render them resistant, whereas kinase dead AXL lines retain sensitivity, 4) therapeutic targeting of AXL can restore sensitivity to cetuximab in the resistant setting and 5) a unique mechanism of resistance is identified where AXL activates Src Family Kinases (SFKs) leading to sustained HER3 signaling. In this proposal we hypothesize that AXL plays an important role in HNC pathogenesis and therapeutic resistance to cetuximab and that AXL mediates resistance by activating the HER3/PI3K/Akt axis via SFKs. To test this hypothesis, we will determine 1) if AXL mediates cetuximab resistance in HNC via a unique circuit involving the SFKs and HER3 (2) If targeting AXL in cetuximab-resistant HNC tumors can increase the efficacy of cetuximab in HNC (3) if AXL serves as a biomarker for cetuximab-resistance in HNC and 4) if cetuximab-resistant tumors, taken directly from patients, can be sensitized to cetuximab by inhibiting AXL signaling. To carry out these studies we have assembled a strong team of molecular biologists, translational physician-scientists, pathologists and biostatisticians. This investigative strategy holds great promise for translation to the clinic and brings innovation by leveraging new molecular insights to a significant existing problem in HNC.

项目概要 该提案的主要目的是检查受体酪氨酸激酶 AXL 作为西妥昔单抗的驱动因素 头颈癌 (HNC) 的耐药性。西妥昔单抗是一种针对 EGFR 的单克隆抗体， 唯一批准用于治疗 HNC 的分子靶向药物。尽管有良好的效益， 大多数患者对西妥昔单抗没有反应，而有反应的患者最终表现出耐药性。 对西妥昔单抗的内在和获得性耐药是改善 HNSCC 治疗结果的主要障碍。 此外，对西妥昔单抗耐药机制的有限分子理解揭示了知识空白 HNC 治疗。为了确定 HNC 中西妥昔单抗耐药的新的、可靶向的机制，我们采用了人类 肿瘤、患者来源的异种移植物（PDX）以及几种内在和获得性耐药模型。我们有 确定 1) AXL 在 HNC 中过度表达，并且与较高的病理分级显着相关， 转移和较短的生存期，2) 与西妥昔单抗耐药的 PDX 相比，AXL 表达较高 西妥昔单抗敏感的 PDX 和 AXL 阻断可以使耐药肿瘤重新敏感，3）AXL 在 西妥昔单抗敏感的 HNC 细胞系使其产生耐药性，而激酶死亡的 AXL 细胞系保留敏感性，4) AXL 的治疗靶向可以恢复耐药环境中对西妥昔单抗的敏感性，5) 独特的 确定了 AXL 激活 Src 家族激酶 (SFK) 导致持续耐药的机制 HER3 信号传导。在此提议中，我们假设 AXL 在 HNC 发病机制中发挥重要作用 西妥昔单抗的治疗耐药性，AXL 通过激活 HER3/PI3K/Akt 介导耐药性 通过 SFK 的轴。为了检验这一假设，我们将确定 1) AXL 是否通过 AXL 介导 HNC 中的西妥昔单抗耐药性 涉及 SFK 和 HER3 的独特电路 (2) 如果在西妥昔单抗耐药的 HNC 肿瘤中靶向 AXL，可以 如果 AXL 作为 HNC 中西妥昔单抗耐药性的生物标志物，则可提高西妥昔单抗在 HNC 中的疗效 (3) 4) 如果直接取自患者的西妥昔单抗耐药肿瘤可以通过抑制而对西妥昔单抗敏感 AXL 信号。为了进行这些研究，我们组建了一支强大的分子生物学家团队， 转化医学科学家、病理学家和生物统计学家。这个调查策略很有效 有望转化为临床，并通过利用新的分子见解来带来创新 HNC 中存在的问题。