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

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.)