BACKGROUND Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical benefit of targeting Src is significantly dampened in HNSCC patients, because the cytotoxic effects of anti-Src therapy and tumor resistance to it are less predictable. Thus, understanding the mechanism of tumor resistance to Src inhibition and seeking a way to overcome it are warranted. METHODS Dual drug-loaded nanoparticles (NPs) were developed to co-deliver Src inhibitor saracatinib (AZD0530) and AKT inhibitor capivasertib (AZD5363) into the same population of tumor cells. An orthotopic tongue tumor model was generated to evaluate the in vivo therapeutic effects. Cell growth was determined by CellTiter-Glo® Luminescent Cell Viability Kit, colony formation, and 3D culture, and tumor growth was determined by bioluminescence and tumor size. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. RESULTS Capivasertib inactivated the AKT-S6 signaling and re-sensitized saracatinib-resistant HNSCC cells to saracatinib. Combination of capivasertib with saracatinib suppressed HNSCC growth more efficiently than either drug alone. Cathepsin B-sensitive NPs for co-delivering saracatinib and capivasertib significantly improved the efficacy of tumor repression without increasing side effects, which were due to highly specific tumor-targeting drug delivery system and synergistic anticancer effects by co-inactivation of AKT and Src in HNSCC cells. CONCLUSIONS Addition of AKT blockade improves anti-HNSCC efficacy of anti-Src therapy, and co-delivery of capivasertib and saracatinib by tumor-targeting NPs has the potential to achieve better treatment outcomes than the free drug combination.

中文翻译：

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通过沙拉替尼/ capivasertib共输送纳米粒子同时灭活Src和AKT，以提高抗Src治疗头颈部鳞状细胞癌的功效。

背景技术Src是一种驱动头颈鳞状细胞癌（HNSCC）进展的癌蛋白，通常在该疾病中被过度激活。不幸的是，在HNSCC患者中靶向Src的临床益处被大大削弱，因为抗Src疗法的细胞毒性作用和肿瘤对其的耐药性难以预测。因此，有必要了解肿瘤对Src抑制的抗性机制并寻求克服它的方法。方法开发了双重载药纳米颗粒（NPs），以将Src抑制剂saracatinib（AZD0530）和AKT抑制剂capivasertib（AZD5363）共递送到相同的肿瘤细胞群中。生成原位舌肿瘤模型以评估体内治疗效果。细胞生长通过CellTiter-Glo®发光细胞生存力试剂盒，集落形成，和3D培养，并通过生物发光和肿瘤大小确定肿瘤的生长。通过蛋白质印迹和免疫组织化学评估了由治疗引起的分子变化。结果Capivasertib灭活了AKT-S6信号传导，并使抗saracatinib的HNSCC细胞重新敏感于saracatinib。与单独使用任何一种药物相比，capivasertib与saracatinib的组合都能更有效地抑制HNSCC的生长。组织蛋白酶B敏感的NP共同递送saracatinib和capivasertib可以显着提高肿瘤抑制的功效而不会增加副作用，这是由于高度特异性的靶向肿瘤的药物递送系统以及HNSCC中AKT和Src共同失活所产生的协同抗癌作用细胞。结论加用AKT阻滞剂可提高抗Src疗法的抗HNSCC疗效，