Splice-Switching Antisense Oligonucleotides Targeting Extra- and Intracellular Domains of Epidermal Growth Factor Receptor in Cancer Cells

Akilandeswari Ashwini Balachandran; Prithi Raguraman; Kamal Rahimizadeh; Rakesh N Veedu

doi:10.3390/biomedicines11123299

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Splice-Switching Antisense Oligonucleotides Targeting Extra- and Intracellular Domains of Epidermal Growth Factor Receptor in Cancer Cells

Journal article

Open access

Peer reviewed

Splice-Switching Antisense Oligonucleotides Targeting Extra- and Intracellular Domains of Epidermal Growth Factor Receptor in Cancer Cells

Akilandeswari Ashwini Balachandran, Prithi Raguraman, Kamal Rahimizadeh and Rakesh N Veedu

Biomedicines, Vol.11(12), 3299

2023

DOI: https://doi.org/10.3390/biomedicines11123299

PMID: 38137520

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Abstract

splice-switching antisense oligonucleotides

breast cancer

liver cancer

glioblastoma

epidermal growth factor receptor

Cancer is one of the leading causes of death globally. Epidermal growth factor receptor is one of the proteins involved in cancer cell proliferation, differentiation, and invasion. Antisense oligonucleotides are chemical nucleic acids that bind to target messenger ribonucleic acid and modulate its expression. Herein, we demonstrate the efficacy of splice-modulating antisense oligonucleotides to target specific exons in the extracellular (exon 3) and intracellular (exon 18, 21) domains of epidermal growth factor receptor. These antisense oligonucleotides were synthesized as 25mer 2'-O methyl phosphorothioate-modified ribonucleic acids that bind to complementary specific regions in respective exons. We found that PNAT524, PNAT525, PNAT576, and PNAT578 effectively skipped exon 3, exon 18, and exon 21 in glioblastoma, liver cancer, and breast cancer cell lines. PNAT578 treatment also skipped partial exon 19, complete exon 20, and partial exon 21 in addition to complete exon 21 skipping. We also found that a cocktail of PNAT576 and PNAT578 antisense oligonucleotides performed better than their individual counterparts. The migration potential of glioblastoma cancer cells was reduced to a greater extent after treatment with these antisense oligonucleotides. We firmly believe that using these splice-modulating antisense oligonucleotides in combination with existing EGFR-targeted therapies could improve therapeutic outcomes.

Details

Title: Splice-Switching Antisense Oligonucleotides Targeting Extra- and Intracellular Domains of Epidermal Growth Factor Receptor in Cancer Cells
Authors/Creators: Akilandeswari Ashwini Balachandran - Perron Institute for Neurological and Translational Science
Prithi Raguraman - Murdoch University
Kamal Rahimizadeh - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
Rakesh N Veedu - Perron Institute for Neurological and Translational Science, Perth, WA 6009, Australia
Publication Details: Biomedicines, Vol.11(12), 3299
Publisher: MDPI
Grant note: MIPS / Murdoch University Forrest scholarship / Forrest research Foundation
Identifiers: 991005623669407891
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: 2 Chemistry; 2.170 Nucleic Acids Chemistry; 2.170.988 Oligonucleotide Modifications
Web Of Science research areas: Biochemistry & Molecular Biology; Medicine, Research & Experimental; Pharmacology & Pharmacy
ESI research areas: Pharmacology & Toxicology