Inhibiting mutant KRAS G12D gene expression using novel peptide nucleic acid-based antisense: A potential new drug candidate for pancreatic cancer.
KRAS
drug candidate
pancreatic cancer
peptide nucleic acid
peptide nucleic acids
Journal
Oncology letters
ISSN: 1792-1082
Titre abrégé: Oncol Lett
Pays: Greece
ID NLM: 101531236
Informations de publication
Date de publication:
Apr 2022
Apr 2022
Historique:
received:
23
08
2021
accepted:
02
02
2022
entrez:
7
3
2022
pubmed:
8
3
2022
medline:
8
3
2022
Statut:
ppublish
Résumé
KRAS mutations, which are the main cause of the pathogenesis of lethal pancreatic adenocarcinomas, impair the functioning of the GTPase subunit, thus rendering it constitutively active and signaling intracellular pathways that end with cell transformation. In the present study, the AsPC-1 cell line, which has a G12D-mutated KRAS gene sequence, was utilized as a cellular model to test peptide nucleic acid-based antisense technology. The use of peptide nucleic acids (PNAs) that are built to exhibit improved hybridization specificity and have an affinity for complementary RNA and DNA sequences, as well as a simple chemical structure and high biological stability that affords resistance to nucleases and proteases, enabled targeting of the KRAS-mutated gene to inhibit its expression at the translation level. Because PNA-based antisense molecules should be capable of binding to KRAS mRNA sequences, PNAs were utilized to target the mRNA of the mutated KRAS gene, a strategy that could lead to the development of a novel drug for pancreatic cancer. Moreover, it was demonstrated that introducing new PNA to cells inhibited the growth of cancer cells and induced apoptotic death and, notably, that it can inhibit G12D-mutated KRAS gene expression, as demonstrated by RT-PCR and western blotting. Altogether, these data strongly suggest that the use of PNA-based antisense agents is an attractive therapeutic approach to treating KRAS-driven cancers and may lead to the development of novel drugs that target the expression of other mutated genes.
Identifiants
pubmed: 35251350
doi: 10.3892/ol.2022.13250
pii: OL-23-04-13250
pmc: PMC8895471
doi:
Types de publication
Journal Article
Langues
eng
Pagination
130Informations de copyright
Copyright: © Shai et al.
Déclaration de conflit d'intérêts
AR and MF are the founders of GeneArrest, Ltd., the IP owner of the novel monomers. We declare that the funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The other authors declare no conflicts of interest.
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