非小细胞肺癌（NSCLC）通常携带表皮生长因子受体（EGFR）的活性突变。针对EGFR酪氨酸激酶活性的药物已经显示出有效抑制携带EGFR突变的癌细胞生长的功效。然而，癌细胞中的额外突变的发展往往导致疾病持续存在，需要采取其他策略来克服这一挑战。我们探索了稳定EGFR启动子区域中形成的G四链体结构以抑制其表达并阻止携带EGFR突变的癌细胞生长的功效。我们发现，碳并苯并（四嗪）衍生物BMVC-8C3O有效抑制了EGFR的表达，并在细胞培养和小鼠异种移植模型中显示出显著的生长抑制作用。重要的是，观察到的EGFR表达抑制和生长抑制不仅限于碳并苯并（四嗪）衍生物，几个其他的G四链体配体也表现出类似的效果。BMVC-8C3O的生长抑制活性部分归因于对EGFR的抑制，尽管可能还会影响到其他细胞靶点。令人惊讶的是，即使在奥西替尼耐药细胞中也观察到了生长抑制效应，表明BMVC-8C3O对于治疗耐药NSCLC具有潜力。我们的研究结果提出了一种有前景和创新的方法，通过有效抑制EGFR表达来抑制携带EGFR突变的NSCLC细胞的生长。本研究中G四链体配体的显示功效突出了它们作为进一步发展NSCLC治疗候选药物的潜力。版权所有 © 2023 Elsevier Inc. 发布。

Non-small cell lung carcinomas (NSCLCs) commonly harbor activating mutations in the epidermal growth factor receptor (EGFR). Drugs targeting the tyrosine kinase activity of EGFR have shown effectiveness in inhibiting the growth of cancer cells with EGFR mutations. However, the development of additional mutations in cancer cells often leads to the persistence of the disease, necessitating alternative strategies to overcome this challenge. We explored the efficacy of stabilizing the G-quadruplex structure formed in the promoter region of EGFR as a means to suppress its expression and impede the growth of cancer cells with EGFR mutations. We revealed that the carbazole derivative BMVC-8C3O effectively suppressed EGFR expression and demonstrated significant growth inhibition in EGFR-mutated NSCLC cells, both in cell culture and mouse xenograft models. Importantly, the observed repression of EGFR expression and growth inhibition were not exclusive to carbazole derivatives, as several other G-quadruplex ligands exhibited similar effects. The growth-inhibitory activity of BMVC-8C3O is attributed, at least in part, to the repression of EGFR, although it is possible that additional cellular targets are also affected. Remarkably, the growth-inhibitory effect was observed even in osimertinib-resistant cells, indicating that BMVC-8C3O holds promise for treating drug-resistant NSCLC. Our findings present a promising and innovative approach for inhibiting the growth of NSCLC cells with EGFR mutations by effectively suppressing EGFR expression. The demonstrated efficacy of G-quadruplex ligands in this study highlights their potential as candidates for further development in NSCLC therapy.Copyright © 2023. Published by Elsevier Inc.