KRAS mutant allele-specific expression knockdown in pancreatic cancer model with systemically delivered bi-shRNA KRAS lipoplex

PloS One
Donald D RaoJohn Nemunaitis

Abstract

The KRAS oncogene, present in over 90% of pancreatic ductal adenocarcinomas, is most frequently the result of one of three gain-of-function substitution mutations of codon 12 glycine. Thus far, RAS mutations have been clinically refractory to both direct and selective inhibition by systemic therapeutics. This report presents the results of pre-clinical assessment of a lipoplex comprising a plasmid-encoded, modular bi-functional shRNA (bi-shRNA), which executes selective and multi-mutant allelic KRASG12mut gene silencing, encased within a fusogenic liposome systemic delivery vehicle. Using both a dual luciferase reporter system and a Restriction Fragment Length Polymorphism (RFLP) assay, selective discrimination of KRASG12mut from KRASwt was confirmed in vitro in PANC1 cells. Subsequently, systemic administration of the bi-shRNAKRAS fusogenic lipoplex into female athymic Nu/Nu mice bearing PANC1 xenografts demonstrated intratumoral plasmid delivery, KRASG12mut knockdown, and inhibition of tumor growth, without adverse effect. Clinical trials with the bi-shRNA lipoplex have been implemented.

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Citations

Sep 3, 2019·Current Topics in Medicinal Chemistry·Fengqian ChenQi Liu
Jan 23, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·David VetvickaDavid Oupický
Feb 24, 2020·Biomaterials·John KokkinosPhoebe A Phillips

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Methods Mentioned

BETA
Assay
transfection
restriction digest
PCR
chip
xenograft
xenografts
antisense oligonucleotide

Software Mentioned

Experion
Image J

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