miR-34c-3p targets CDK1 a synthetic lethality partner of KRAS in non-small cell lung cancer

Abstract

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 KRASmut 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 KRASmut-expressing cells. Altogether, our findings demonstrate that miR-34c-3p is a novel biomarker that may allow tailored treatment for KRAS-mutated NSCLC patients.

Exosomal microRNAs synergistically trigger stromal fibroblasts in breast cancer

“…For example, the tumor suppressor miR-34 family is recognized as one of the most significant in cancer and is investigated in numerous pre-clinical and clinical studies. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 A miR-34a mimic-based drug was employed in the MRX34 clinical trial (NCT01829971), which was the first-in-human phase 1 study of miRNA-based cancer therapy. 30 Even though the clinical trial terminated prematurely, it was the first concrete application of miRNAs in the clinic and a solid proof of concept for miRNA-based cancer therapy.…”

Comprehensive Analysis of CDK1-Associated ceRNA Network Revealing the Key Pathways LINC00460/LINC00525-Hsa-Mir-338-FAM111/ZWINT as Prognostic Biomarkers in Lung Adenocarcinoma Combined with Experiments

“…CDK1 is an important cell cycle regulatory protein, which is a key factor in the G2/M phase transition in cell mitosis [ 27 , 28 , 29 ]. High expression of CDK1 is related to the occurrence and poor prognosis of colorectal, liver, lung and pancreatic cancer [ 30 , 31 , 32 , 33 , 34 ]. However, CDK1 inhibitors can prevent cell division and promote cancer cell apoptosis and tumor regression [ 35 , 36 ].…”

Expression and Diagnostic Efficacy of miR-126-5p and miR-34c-3p in Serum Extracellular Vesicles of Non-Small Cell Lung Cancer Patients

“…LUAD with higher miR-34a/b/c levels had better OS [46,47]. miR-34c-3p is a new biomarker for NSCLC patients [21]. In conclusion, miR-126-5p and miR-34c-3p in serum EVs may be applied as diagnostic markers for NSCLC and are related to the prognosis.…”

“…Besides, miR-34c-3p is downregulated both in NSCLC tissues and cell lines [19,20]. miR-34c-3p is a prognostic factor in KRAS-mutated NSCLC patients and its high expression is linked with longer survival [21]. Exosomesshuttled low miR-34c-3p is implicated in NSCLC progression [22].…”