PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.
摘要：
胰腺导管腺癌（PDAC）在诊断和治疗方面提出了重大挑战，治疗选择有限，预后不良。这项研究探索了NPS-1034的潜在治疗作用，一种针对MET和AXL的激酶抑制剂，在PDAC。研究包括NPS-1034的单药治疗及其与常用化疗药物的联合治疗。氟尿嘧啶和奥沙利铂。我们的研究表明，NPS-1034以剂量依赖的方式诱导细胞死亡并降低PDAC细胞的活力和克隆形成性。此外，NPS-1034通过抑制MET/PI3K/AKT轴诱导的上皮-间质转化(EMT)来抑制PDAC细胞的迁移。NPS-1034与氟尿嘧啶或奥沙利铂的组合显示出协同作用，与单一疗法相比，显着降低细胞活力并诱导肿瘤细胞凋亡。下一代测序提供的机制见解表明，NPS-1034通过诱导PDAC细胞中I型干扰素和肿瘤坏死因子的产生来调节免疫应答。这表明NPS-1034除了MET和AXL抑制外还有更广泛的作用，将其定位为潜在的免疫调节剂。总的来说,这些发现强调了NPS-1034在体外PDAC治疗中的抗癌潜力，无论是作为单一疗法还是与传统化疗相结合，为临床探索之前的进一步体内研究提供了一个有希望的途径。
