GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis.
GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis.
复制标题
AVB-500抑制GAS 6-AXL通过减少肿瘤细胞糖酵解克服子宫内膜癌对紫杉醇的耐药性。
DOI：
10.1158/1535-7163.mct-21-0704
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发表时间：
2022-08-02
影响因子：
5.7
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中科院分区：
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化疗往往是无效的晚期和侵袭性组织学亚型的子宫内膜癌。已发现受体酪氨酸激酶AXL的过表达与治疗抗性、转移和不良预后相关。然而，抑制AXL如何改善对化疗的反应的机制在很大程度上仍然未知。因此，我们的目的是确定是否与AVB-500，GAS 6-AXL的选择性抑制剂治疗，提高子宫内膜癌细胞化疗的敏感性，特别是通过代谢的变化。我们通过免疫组化发现，与对化疗反应良好的肿瘤相比，对化疗反应较差的肿瘤患者的GAS 6和AXL表达更高。我们发现，当与AVB-500联合治疗时，化疗耐药的子宫内膜癌细胞（ARK 1，子宫浆液性癌和PUC 198，3级卵巢样腺癌）对紫杉醇和卡铂的敏感性和协同作用有所改善。我们还发现，与紫杉醇单独治疗相比，用AVB-500 +紫杉醇治疗ARK 1和PUC 198细胞的体内腹膜内模型具有降低的肿瘤负荷。用AVB-500 +紫杉醇治疗降低AKT信号传导，这导致基础糖酵解减少。最后，在用AVB-500 +紫杉醇治疗的肿瘤中，多种糖酵解代谢物低于用紫杉醇单独治疗的肿瘤。我们的研究为AVB-500与紫杉醇联合治疗侵袭性子宫内膜癌模型提供了强有力的临床前依据。
Chemotherapy is often ineffective in advanced stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis. However, the mechanism of how inhibition of AXL improves response to chemotherapy is still largely unknown. Thus, we aimed to determine whether treatment with AVB-500, a selective inhibitor of GAS6-AXL, improves endometrial cancer cell sensitivity to chemotherapy particularly through metabolic changes. We found that both GAS6 and AXL expression were higher by immunohistochemistry in patient tumors with a poor response to chemotherapy compared to tumors with a good response to chemotherapy. We showed that chemotherapy resistant endometrial cancer cells (ARK1, uterine serous carcinoma and PUC198, grade 3 endometrioid adenocarcinoma) had improved sensitivity and synergy with paclitaxel and carboplatin when treated in combination with AVB-500. We also found that in vivo intraperitoneal models with ARK1 and PUC198 cells had decreased tumor burden when treated with AVB-500 + paclitaxel compared to paclitaxel alone. Treatment with AVB-500 + paclitaxel decreased AKT signaling which resulted in a decrease in basal glycolysis. Finally, multiple glycolytic metabolites were lower in the tumors treated with AVB-500 + paclitaxel than in tumors treated with paclitaxel alone. Our study provides strong pre-clinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models.