Lung cancer is still the leading cause of death by cancer worldwide despite advances both in its detection and therapy. Multiple oncogenic driver alterations have been discovered, opening the prospective for new potential therapeutic targets. Among them, KRAS mutations represent the most frequent oncogene aberrations in non-small cell lung cancer (NSCLC) patients with a negative prognostic impact, but effective therapies targeting KRAS are not well characterized yet. Here, we demonstrate that the microRNA miR-34c-3p is a positive prognostic factor in KRAS-mutated NSCLC patients. Firstly, looking at the TGCA dataset, we found that high miR-34c-3p expression correlated with longer survival of KRAS-mutated NSCLC patients. In vitro assays on immortalized and patient-derived primary NSCLC cells revealed that miR-34c-3p overexpression increased apoptosis and lowered proliferation rate in KRAS^mut cells. Computational analysis and in vitro assays identified CDK1, one of the most promising lethal targets for KRAS-mutant cancer, as a target of miR-34c-3p. Moreover, the combination of CDK1 inhibition (mediated by RO3306) and miR-34c-3p overexpression resulted in an additive effect on the viability of KRAS^mut-expressing cells. Altogether, our findings demonstrate that miR-34c-3p is a novel biomarker that may allow tailored treatment for KRAS-mutated NSCLC patients.

尽管肺癌的检测和治疗都取得了进展，但肺癌仍然是全球癌症死亡的主要原因。已经发现了多种致癌驱动因素的改变，为新的潜在治疗靶点开辟了前景。其中，KRAS 突变代表了非小细胞肺癌 (NSCLC) 患者中最常见的癌基因畸变，对预后有负面影响，但针对 KRAS 的有效疗法尚未得到很好的表征。在这里，我们证明 microRNA miR-34c-3p 是 KRAS 突变的 NSCLC 患者的阳性预后因素。首先，查看 TGCA 数据集，我们发现高 miR-34c-3p 表达与 KRAS 突变的 NSCLC 患者的较长生存期相关。^mut细胞。计算分析和体外试验确定 CDK1 是 miR-34c-3p 的靶标，CDK1 是 KRAS 突变癌症最有希望的致死靶标之一。此外，CDK1 抑制（由 RO3306 介导）和 miR-34c-3p 过表达的组合对 KRAS ^mut表达细胞的活力产生了累加效应。总之，我们的研究结果表明，miR-34c-3p 是一种新的生物标志物，可以为 KRAS 突变的 NSCLC 患者提供量身定制的治疗。