Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Clin Cancer Res. 2020 Aug 15;26(16):4349-4359. doi: 10.1158/1078-0432.CCR-19-3142. Epub 2020 May 21.
Radiation and cetuximab are therapeutics used in management of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of this disease. The purpose of this study was to investigate signaling of the receptor tyrosine kinase AXL in resistance to radiation and cetuximab treatment.
To study AXL signaling in the context of treatment-resistant HNSCC, we used patient-derived xenografts (PDXs) implanted into mice and evaluated the tumor response to AXL inhibition in combination with cetuximab or radiation treatment. To identify molecular mechanisms of how AXL signaling leads to resistance, three tyrosine residues of AXL (Y779, Y821, Y866) were mutated and examined for their sensitivity to cetuximab and/or radiation. Furthermore, reverse phase protein array (RPPA) was employed to analyze the proteomic architecture of signaling pathways in these genetically altered cell lines.
Treatment of cetuximab- and radiation-resistant PDXs with AXL inhibitor R428 was sufficient to overcome resistance. RPPA analysis revealed that such resistance emanates from signaling of tyrosine 821 of AXL via the tyrosine kinase c-ABL. In addition, inhibition of c-ABL signaling resensitized cells and tumors to cetuximab or radiotherapy even leading to complete tumor regression without recurrence in head and neck cancer models.
Collectively, the studies presented herein suggest that tyrosine 821 of AXL mediates resistance to cetuximab by activation of c-ABL kinase in HNSCC and that targeting of both EGFR and c-ABL leads to a robust antitumor response.
辐射和西妥昔单抗是用于治疗头颈部鳞状细胞癌（HNSCC）的治疗方法。尽管这些方法在临床上取得了成功，但内在和获得性耐药的发展是该疾病治疗中一个新出现的问题。本研究的目的是研究受体酪氨酸激酶 AXL 的信号转导在辐射和西妥昔单抗治疗耐药中的作用。
为了研究治疗耐药性 HNSCC 中的 AXL 信号转导，我们使用患者来源的异种移植物（PDXs）植入小鼠中，并评估 AXL 抑制与西妥昔单抗或放射治疗联合治疗的肿瘤反应。为了确定 AXL 信号转导导致耐药的分子机制，我们突变了 AXL 的三个酪氨酸残基（Y779、Y821、Y866），并检查了它们对西妥昔单抗和/或辐射的敏感性。此外，还采用反相蛋白阵列（RPPA）分析这些基因改变的细胞系中信号通路的蛋白质组结构。
用 AXL 抑制剂 R428 治疗西妥昔单抗和放疗耐药的 PDXs 足以克服耐药性。RPPA 分析表明，这种耐药性源于 AXL 的酪氨酸 821 通过酪氨酸激酶 c-ABL 发出信号。此外，抑制 c-ABL 信号转导可使细胞和肿瘤对西妥昔单抗或放疗重新敏感，甚至导致头颈部癌症模型中完全肿瘤消退而无复发。
总之，本文研究表明，AXL 的酪氨酸 821 通过激活 HNSCC 中的 c-ABL 激酶介导对西妥昔单抗的耐药性，而靶向 EGFR 和 c-ABL 均可导致强大的抗肿瘤反应。
