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Published on: June 26, 2019
Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer
Brian J Thomas1, Caitlyn Guldenpfennig1, Yue Guan1
1Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, 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.
Insights
This study shows that the MinE07 aptamer effectively targets non-small cell lung cancer (NSCLC) cells with EGFR mutations. MinE07 shows promise as a reagent for NSCLC recognition, even in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Non-small cell lung cancer (NSCLC) often involves epidermal growth factor receptor (EGFR) mutations.
- While EGFR tyrosine kinase inhibitors (TKIs) are used, resistance develops, necessitating alternative targeting strategies.
- There is a need for ligands that target both wild-type and mutant EGFR for improved NSCLC therapy and drug delivery.
Purpose of the Study:
- To evaluate the potential of an anti-EGFR aptamer, MinE07, for targeting NSCLC.
- To assess MinE07's binding characteristics to various EGFR mutations.
- To investigate the efficacy of a bispecific aptamer (bsApt) combining MinE07 with an anti-c-Met aptamer for NSCLC targeting.
Main Methods:
- Characterization of MinE07 binding sites on EGFR, including overlap with antibody epitopes.
- Assessment of MinE07 binding to EGFR variants with common oncogenic and resistance mutations.
- In vitro and in vivo evaluation of monospecific MinE07 and a bispecific aptamer (bsApt) for NSCLC cell and xenograft targeting.
- Biodistribution studies of differently labeled bsApt constructs.
Main Results:
- MinE07 binding sites overlap with clinically relevant antibody targets on EGFR.
- MinE07 successfully binds to EGFR with common oncogenic and resistance mutations.
- The bsApt demonstrated superior in vitro NSCLC cell labeling compared to monospecific aptamers.
- In vivo dual targeting did not enhance NSCLC xenograft recognition over MinE07 alone.
- Significant differences in biodistribution were observed between differently labeled bsApt formulations.
Conclusions:
- MinE07 aptamer formulations can target ectopic lung cancer effectively without stabilization.
- MinE07 shows potential as a targeting reagent for NSCLC, particularly for tumors with clinically relevant EGFR mutations.
- Further development of aptamer-based strategies for NSCLC holds promise for targeted therapy and drug delivery.
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