Non-small cell lung cancer (NSCLC) caused more deaths in 2017 than breast cancer, prostate, and brain cancers combined. This is primarily due to their aggressive metastatic nature, leading to more fatal rates of cancer patients. Despite this condition, there are no clinically approved drugs that can target metastasis. The NSCLC with EGFR T790M-overexpressing HER2 shows the resistance to osimertinib and trastuzumab starting 10–18 months after the therapy, and thus prospects are grim to these patients. To target the recalcitrant ERBB2 driver oncogene, we developed two engineered destabilizing 3'UTR ERBB2 constructs that degrade the endogenous ERBB2 transcript and proteins by overwriting the encoded endogenous ERBB2 mRNA with the destabilizing message. When iron oxide nanocages (IO nanocages) were used as vehicles to deliver them to tumors and whole tissues in mice bearing tumors, it was well tolerated and safe and caused no genome rearrangement whereas they were integrated into genome deserts (non-coding regions). We achieved significant reduction of the primary tumor volume with desARE3'UTRERBB2-30, achieving 50% complete tumor lysis and inhibiting 60%–80% of liver metastasis, hepatomegaly, and 90% of lung metastasis, through ERBB2 downregulation. These constructs were distributed robustly into tumors, livers, lungs, kidneys, and spleen and mildly in the brain and not in the heart. They caused no abnormality in both short- and long-term administrations as well as in healthy mice. In summary, we accomplished significant breakthrough for the therapeutics of intractable lung cancer patients whose cancers become resistant and metastasize.

中文翻译：

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ERBB2 的 Nanocage 工程化不稳定 3'UTR ARE 通过减少 ERBB2 抑制 EGFR T790M 奥希替尼和曲妥珠单抗耐药以及表达 ERBB2 的 NSCLC 中的肿瘤生长以及肝和肺转移

2017 年，非小细胞肺癌 (NSCLC) 造成的死亡人数比乳腺癌、前列腺癌和脑癌的总和还多。这主要是由于它们的侵袭性转移性质，导致癌症患者的死亡率更高。尽管存在这种情况，但临床上还没有批准的药物可以靶向转移。 EGFR T790M 过度表达 HER2 的 NSCLC 在治疗后 10-18 个月开始显示出对奥西替尼和曲妥珠单抗的耐药性，因此这些患者的前景严峻。为了针对顽固的 ERBB2 驱动癌基因，我们开发了两种工程化的不稳定 3'UTR ERBB2 构建体，它们通过用不稳定信息覆盖编码的内源 ERBB2 mRNA 来降解内源 ERBB2 转录物和蛋白质。当氧化铁纳米笼（IO 纳米笼）用作载体将其递送至荷瘤小鼠的肿瘤和整个组织时，它具有良好的耐受性和安全性，并且不会引起基因组重排，而它们被整合到基因组荒漠（非编码区）中。我们使用 desARE3'UTRERBB2-30 显着缩小了原发肿瘤体积，通过下调 ERBB2，实现了 50% 的肿瘤完全溶解，并抑制了 60%–80% 的肝转移、肝肿大和 90% 的肺转移。这些构建体广泛分布在肿瘤、肝脏、肺、肾脏和脾脏中，并且少量分布在大脑中，而不是心脏中。它们在短期和长期给药以及健康小鼠中均未引起异常。总之，我们在癌症耐药和转移的难治性肺癌患者的治疗方面取得了重大突破。