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

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

  • EBioMedicine. 2024 Oct:108:105356. doi: 10.1016/j.ebiom.2024.105356.
Trinh T T Tran 1,  Cao Dai Phung 1,  Brendon Z J Yeo 1,  Rebecca C Prajogo 1,  Migara K Jayasinghe 2,  Ju Yuan 3,  Daniel S W Tan 4,  Eric Y M Yeo 1,  Boon Cher Goh 2,  Wai Leong Tam 5,  Minh T N Le 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore, 138672, Republic of Singapore.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 39303667 DOI: 10.1016/j.ebiom.2024.105356
Abstract

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.

Keywords

Antisense oligonucleotides; Cancer therapy; EGFR; Extracellular vesicles; Non-small cell lung cancer.

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