Customised design of antisense oligonucleotides targeting EGFR driver mutants for personalised treatment of non-small cell lung cancer.

Autor:	Tran TTT; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore., Phung CD; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore., Yeo BZJ; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore., Prajogo RC; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore., Jayasinghe MK; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore., Yuan J; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore, 138672, Republic of Singapore., Tan DSW; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore, 138672, Republic of Singapore; Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Republic of Singapore; Duke-NUS Medical School, Republic of Singapore, 8 College Road, Singapore, 169857, Republic of Singapore; Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Republic of Singapore; Cancer and Therapeutics Research Laboratory, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Republic of Singapore., Yeo EYM; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore., Goh BC; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore., Tam WL; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore; Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore, 138672, Republic of Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore. Electronic address: tamwl@gis.a-star.edu.sg., Le MTN; Department of Pharmacology and Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Republic of Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore, 119228, Republic of Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research, (A∗STAR), 61 Biopolis Street, Proteos, Singapore, 138673, Republic of Singapore. Electronic address: phcltnm@nus.edu.sg.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Oct; Vol. 108, pp. 105356. Date of Electronic Publication: 2024 Sep 19.
DOI:	10.1016/j.ebiom.2024.105356
Abstrakt:	Background: Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC. Methods: In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells. Findings: Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour. Interpretation: Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment. Funding: This study was funded by Singapore's Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education. Competing Interests: Declaration of interests M.T.N.L is a cofounder and advisor of Carmine Therapeutics, which develops gene therapy, and has a patent relating to Vesicle-Based Compositions and Uses Thereof. Carmine Therapeutics provides a proprietary transfection reagent required for loading of ASOs into EVs used in this study. C.D.P has a patent relating to Vesicle-Based Compositions and Uses Thereof. M.K.J has received consulting fees from Jotbody HK Ltd and patent royalties from Carmine Therapeutics. He also has two pending patents filed with NUS ILO and NTUITIVE pertaining to EVs. B.C.G has a patent relating to Modulation of Signal Transducer and Activator of Transcription 3 (STAT3) Expression. D.S.W.T has received grants from ACM Biolabs, Amgen, Astra Zeneca, Bayer and Pfizer, consulting fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche and Takeda, honoraria from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, BeiGene, Regeneron and Zymeworks. He has also obtained support for travel from Bayer, Merck, Pfizer, Regeneron and Zymeworks. Other authors declare no competing financial interest. (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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