Mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene drives the development of lung cancer. EGFR tyrosine kinase inhibitors (EGFR TKIs), including erlotinib and afatinib, are initially effective in treating EGFR mutant nonsmall cell lung cancer (NSCLC). However, drug resistance quickly develops due to several mechanisms, including induction of the epithelial-mesenchymal transition (EMT). No effective therapies are currently available for patients who develop EMT-associated EGFR TKI resistance. 1,25-Dihydroxyvitamin D3 (1,25D3) promotes epithelial differentiation and inhibits growth of NSCLC cells. 1,25D3 thus represents a promising agent for the treatment of EMT-associated EGFR TKI resistance. However, 1,25D3 induces the expression of 24-hydroxylase (24OHase), which decreases 1,25D3 activity. CTA091, a potent and selective 24OHase inhibitor, has been developed to attenuate this adverse effect. CTA091 also suppresses renal 24OHase activity and so may promote hypercalcemia. To exploit favorable effects of 1,25D3 plus CTA091 in tumor cells while avoiding problematic systemic effects of 24OHase inhibition, we developed EGFR-targeted, liposomal nanoparticles (EGFR-LP) to offer tumor-targeted co-delivery of 1,25D3 and CTA091. We then established an EMT-associated model of EGFR TKI resistance, and showed that such nanoparticles improved cellular uptake of 1,25D3 and CTA091, drove pro-epithelial signaling by upregulating E-cadherin (CDH1), and significantly inhibited the growth of EGFR TKI resistant cells. Our results demonstrated that the delivery of vitamin D-based drug payloads via tumor-targeted EGFR-LP has promise as a new therapy for EFGR TKI resistant lung cancer. Future studies will focus on in vivo evaluation of biological activity, therapeutic benefits, and systemic toxicity prior to clinical translation.

中文翻译：

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靶向肿瘤的纳米颗粒可提供基于维生素D的药物有效载荷，以治疗EGFR酪氨酸激酶抑制剂耐药的肺癌。

表皮生长因子受体（EGFR）基因的酪氨酸激酶（TK）结构域中的突变驱动肺癌的发展。EGFR酪氨酸激酶抑制剂（EGFR TKI），包括埃洛替尼和阿法替尼，最初可有效治疗EGFR突变型非小细胞肺癌（NSCLC）。然而，由于多种机制，包括上皮-间质转化（EMT）的诱导，耐药性迅速发展。目前尚无有效疗法可用于发生EMT相关的EGFR TKI耐药的患者。1,25-二羟基维生素D3（1,25D3）促进上皮分化并抑制NSCLC细胞的生长。因此，1,25D3代表了一种有前途的治疗EMT相关的EGFR TKI耐药性的药物。但是，1,25D3诱导24-羟化酶（24OHase）的表达，从而降低1,25D3的活性。已经开发出一种有效的选择性24OHase抑制剂CTA091来减轻这种不利影响。CTA091还抑制肾脏的24OHase活性，因此可能促进高钙血症。为了发挥1的有利作用 我们在肿瘤细胞中添加25D3加CTA091的同时避免了24OHase抑制作用的系统性问题，我们开发了以EGFR为靶标的脂质体纳米颗粒（EGFR-LP），以提供以肿瘤为靶标的1,25D3和CTA091共同递送。然后，我们建立了一个与EMT相关的EGFR TKI抗性模型，并表明这种纳米颗粒改善了1,25D3和CTA091的细胞摄取，通过上调E-钙黏着蛋白来驱动上皮促信号转导（CDH1），并显着抑制EGFR TKI耐药细胞的生长。我们的结果表明，通过靶向肿瘤的EGFR-LP递送基于维生素D的药物有效载荷有望成为EFGR TKI耐药性肺癌的新疗法。未来的研究将侧重于在临床翻译之前对生物活性，治疗益处和全身毒性进行体内评估。