Inhibiting mutant KRAS G12D gene expression using novel peptide nucleic acid-based antisense: A potential new drug candidate for pancreatic cancer.

Content Provider	Europe PMC
Author	Shai, Ayelet Galouk, Evleen Miari, Reem Tareef, Hala Sammar, Marei Zeidan, Mouhammad Rayan, Anwar Falah, Mizied
Copyright Year	2022
Abstract	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.
ISSN	17921074
Journal	Oncology Letters
Volume Number	23
PubMed Central reference number	PMC8895471
Issue Number	4
PubMed reference number	35251350
e-ISSN	17921082
DOI	10.3892/ol.2022.13250
Language	English
Publisher	D.A. Spandidos
Publisher Date	2022-02-21
Access Restriction	Open
Rights License	This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Copyright: © Shai et al.
Subject Keyword	pancreatic cancer KRAS peptide nucleic acid peptide nucleic acids drug candidate
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology