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

项目总结 这项建议的主要目的是研究受体酪氨酸激酶Axl作为西妥昔单抗的驱动因素。 头颈癌的耐药性(HNC)。西妥昔单抗是一种针对EGFR的单抗，是 在HNC的管理中只批准了分子靶向药物。尽管有既定的好处，但 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。 西妥昔单抗的内在和获得性耐药是提高HNSCC治疗结果的主要障碍。 此外，对西妥昔单抗耐药机制的分子理解有限，揭示了在 HNC疗法。为了确定西妥昔单抗在HNC中耐药的新的靶向机制，我们使用了 肿瘤、患者来源的异种移植(PDX)以及几种固有和获得性耐药模型。我们有 研究发现：1)AXL在HNC中高表达，并与较高的病理分级显著相关； 转移和较短的生存期，2)与西妥昔单抗耐药的PDX相比，其Ax1的表达更高 西妥昔单抗敏感的PDX和Axl阻断可使耐药肿瘤重新增敏，3)Axl过表达 西妥昔单抗敏感的HNC品系使它们具有抗性，而激酶死亡的Axl品系保持敏感性，4) AXL的治疗靶向可以在耐药环境中恢复对西妥昔单抗的敏感性，5)独特的 AXL激活Src家族激酶(SFK)导致持续 HER3信号。在这项建议中，我们假设axl在HNC的发病机制中起重要作用。 和西妥昔单抗的治疗耐药，Axl通过激活HER3/PI3K/Akt介导耐药 通过SFK的轴线。为了验证这一假设，我们将确定1)Ax1是否通过一种 涉及SFKs和HER3(2)的独特电路如果靶向西妥昔单抗耐药的HNC肿瘤中的Axl，则可以 提高西妥昔单抗在HNC中的疗效(3)如果Ax1作为HNC西妥昔单抗耐药的生物标志物 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西妥昔单抗而对其敏感 AXL信令。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， 翻译内科医生--科学家、病理学家和生物统计学家。这一调查策略很有说服力 承诺将其转化为临床，并通过利用新的分子洞察力带来创新 HNC中存在的问题。

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.