Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.
Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.
Mol Cancer Ther. 2019 Feb;18(2):389-398. doi: 10.1158/1535-7163.MCT-18-0537. Epub 2018 Nov 26.
Ovarian cancer, one of the deadliest malignancies in female cancer patients, is characterized by recurrence and poor response to cytotoxic chemotherapies. Fewer than 30% of patients with resistant disease will respond to additional chemotherapy treatments. This study aims to determine whether and how inhibition of the receptor tyrosine kinase AXL can restore sensitivity to first-line platinum and taxane therapy in ovarian cancer. AXL staining was quantified in a patient tissue microarray and correlated with chemoresponse of patients. We used small hairpin RNAs to knock down AXL expression and the small-molecule inhibitor BGB324 to inhibit AXL and assessed sensitivity of cell lines and primary patient-derived cells to chemotherapy. We quantified platinum accumulation by inductivity-coupled plasma phase mass spectrometry. Finally, we treated chemoresistant patient-derived xenografts with chemotherapy, BGB324, or chemotherapy plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant patient tumors and cell lines than in chemosensitive tumors and cell lines. AXL staining significantly predicted chemoresponse. Knockdown and inhibition of AXL dose-dependently improved response to paclitaxel and carboplatin in both cell lines and primary cells. AXL inhibition increased platinum accumulation by 2-fold ( < 0.05). studies indicated that AXL inhibition enhanced the ability of chemotherapy to prevent tumor growth (****, < 0.0001). AXL contributes to platinum and taxane resistance in ovarian cancer, and inhibition of AXL improves chemoresponse and accumulation of chemotherapy drugs. This study supports continued investigation into AXL as a clinical target.
卵巢癌是女性癌症患者中最致命的恶性肿瘤之一，其特征是复发和对细胞毒化疗药物的反应不佳。只有不到 30%的耐药患者对额外的化疗治疗有反应。本研究旨在确定抑制受体酪氨酸激酶 AXL 是否以及如何恢复卵巢癌对一线铂类和紫杉烷类治疗的敏感性。在患者组织微阵列中定量检测 AXL 染色，并将其与患者的化疗反应相关联。我们使用短发夹 RNA 敲低 AXL 表达，使用小分子抑制剂 BGB324 抑制 AXL，并评估细胞系和原代患者来源细胞对化疗的敏感性。我们通过电感耦合等离子体质谱法定量检测铂的积累。最后，我们用化疗药物、BGB324 或化疗加 BGB324 治疗化疗耐药的患者来源异种移植瘤，并监测肿瘤负担。耐药患者肿瘤和细胞系中的 AXL 表达高于化疗敏感的肿瘤和细胞系。AXL 染色显著预测化疗反应。AXL 的敲低和抑制在细胞系和原代细胞中均剂量依赖性地改善了对紫杉醇和卡铂的反应。AXL 抑制使铂的积累增加了 2 倍（<0.05）。进一步的研究表明，AXL 抑制增强了化疗预防肿瘤生长的能力（****，<0.0001）。AXL 促进了卵巢癌对铂类和紫杉烷类的耐药性，抑制 AXL 可改善化疗反应和化疗药物的积累。本研究支持继续将 AXL 作为临床靶点进行研究。
