AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer.
AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer.
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DOI：
10.1158/1535-7163.mct-21-0293
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发表时间：
2022-01
影响因子：
5.7
通讯作者：
Brekken RA
中科院分区：
文献类型：
--
作者：
Zhang Y;Arner EN;Rizvi A;Toombs JE;Huang H;Warner SL;Foulks JM;Brekken RA
胰腺癌是美国癌症相关死亡的第三大原因，5年生存率低于5%。由于免疫抑制和富含基质的微环境，对标准疗法的抗性和对免疫检查点阻断的有限反应仍然是胰腺癌治疗的主要挑战。涉及治疗抗性的关键细胞程序是上皮可塑性，其也与侵袭、转移和逃避免疫监视相关。受体酪氨酸激酶AXL是肿瘤细胞上皮可塑性的关键驱动因素。AXL的高表达和活性与包括胰腺癌在内的多种类型的癌症的不良预后、转移和治疗抗性相关。在这里，我们表明AXL抑制剂（TP-0903）在胰腺导管腺癌（PDA）的临床前模型中具有抗肿瘤和治疗增敏作用。我们证明TP-0903作为单一药剂或与吉西他滨和/或抗程序性细胞死亡蛋白1（PD 1）抗体组合在携带PDA肿瘤的小鼠中具有抗转移和抗肿瘤作用，导致存活率增加。此外，肿瘤的基因表达分析表明，与溶媒相比，TP-0903治疗动物的肿瘤中促炎和免疫活化基因上调，表明AXL活化的药理学抑制导致免疫刺激微环境。当TP-0903与吉西他滨和抗PD 1抗体组合时，这种作用增强。这些结果为评价TP-0903治疗胰腺癌提供了明确的依据。
Pancreatic cancer is the 3rd leading cause of cancer-related deaths in the United States with a 5-year survival less than 5%. Resistance to standard therapy and limited response to immune checkpoint blockade due to the immunosuppressive and stroma-rich microenvironment remain major challenges in the treatment of pancreatic cancer. A key cellular program involved in therapy resistance is epithelial plasticity, which is also associated with invasion, metastasis, and evasion of immune surveillance. The receptor tyrosine kinase AXL is a key driver of tumor cell epithelial plasticity. High expression and activity of AXL is associated with poor prognosis, metastasis, and therapy resistance in multiple types of cancer including pancreatic. Here, we show that an AXL inhibitor (TP-0903), has anti-tumor and therapy sensitizing effects in pre-clinical models of pancreatic ductal adenocarcinoma (PDA). We demonstrate that TP-0903 as a single agent or in combination with gemcitabine and/or anti-programmed cell death protein 1 (PD1) antibody has anti-metastatic and anti-tumor effects in PDA tumor bearing mice, leading to increased survival. Additionally, gene expression analysis of tumors demonstrated upregulation of pro-inflammatory and immune activation genes in tumors from TP-0903-treated animals compared to the vehicle, indicating pharmacologic inhibition of AXL activation leads to an immunostimulatory microenvironment. This effect was augmented when TP-0903 was combined with gemcitabine and anti-PD1 antibody. These results provide clear rationale for evaluating TP-0903 in the treatment of pancreatic cancer.