miR-34c-3p targets CDK1 a synthetic lethality partner of KRAS in non-small cell lung cancer.
Cancer Gene Ther
; 28(5): 413-426, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-32948832
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação Neoplásica da Expressão Gênica
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Proteína Quinase CDC2
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Proteínas Proto-Oncogênicas p21(ras)
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Carcinoma Pulmonar de Células não Pequenas
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MicroRNAs
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Mutações Sintéticas Letais
Tipo de estudo:
Observational_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cancer Gene Ther
Assunto da revista:
GENETICA MEDICA
/
NEOPLASIAS
/
TERAPEUTICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Itália