Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer

Brian J Thomas; Caitlyn Guldenpfennig; Yue Guan; Calvin Winkler; Margaret Beecher; Michaela Beedy; Ashley F Berendzen; Lixin Ma; Mark A Daniels; Donald H Burke; David Porciani

doi:10.1016/j.omtn.2023.102046

Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer

Mol Ther Nucleic Acids. 2023 Oct 4:34:102046. doi: 10.1016/j.omtn.2023.102046. eCollection 2023 Dec 12.

Authors

Affiliations

¹ Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USA.
² Department of Biological Sciences, University of Missouri, Columbia, MO 65211, USA.
³ Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
⁴ Department of Biochemistry, Westminster College, Fulton, MO 65251, USA.
⁵ Research Division/Biomolecular Imaging Center, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.
⁶ Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65212, USA.

Abstract

A significant fraction of non-small cell lung cancer (NSCLC) cases are due to oncogenic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Anti-EGFR antibodies have shown limited clinical benefit for NSCLC, whereas tyrosine kinase inhibitors (TKIs) are effective, but resistance ultimately occurs. The current landscape suggests that alternative ligands that target wild-type and mutant EGFRs are desirable for targeted therapy or drug delivery development. Here we evaluate NSCLC targeting using an anti-EGFR aptamer (MinE07). We demonstrate that interaction sites of MinE07 overlap with clinically relevant antibodies targeting extracellular domain III and that MinE07 retains binding to EGFR harboring the most common oncogenic and resistance mutations. When MinE07 was linked to an anti-c-Met aptamer, the EGFR/c-Met bispecific aptamer (bsApt) showed superior labeling of NSCLC cells in vitro relative to monospecific aptamers. However, dual targeting in vivo did not improve the recognition of NSCLC xenografts compared to MinE07. Interestingly, biodistribution of Cy7-labeled bsApt differed significantly from Alexa Fluor 750-labeled bsApt. Overall, our findings demonstrate that aptamer formulations containing MinE07 can target ectopic lung cancer without additional stabilization or PEGylation and highlights the potential of MinE07 as a targeting reagent for the recognition of NSCLC harboring clinically relevant EGFRs.

Keywords: EGFR resistance mutations; MT: Delivery Strategies; aptamers; biodistribution; molecular engineering; non-small cell lung cancer; oligonucleotides; targeted delivery; tumor cell-surface receptors.