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Development of gemcitabine-modified multimodal miR-129 mimic as a novel therapeutic in non-small cell lung cancer
Erick M Intriago1, Amartya Pal1, Anushka Ojha1
1Department of Pathology, Stony Brook Cancer Center, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA.
Abstract:
Resistance to chemotherapy and tyrosine kinase inhibitor (TKI)-based therapy is the main reason for treatment failure in non-small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop novel strategies to combat resistance. In this study, we designed and developed a novel, multi-targeted microRNA (miRNA) approach to overcome resistance to EGFR inhibitors. Specifically, the guide strand of the tumor suppressor miR-129 was modified by replacing cytidine with the nucleoside analog gemcitabine (Gem). The therapeutic potential of Gem-miR-129 was investigated in both in vitro and in vivo NSCLC model systems. Our results demonstrate that Gem-miR-129 is a potent inhibitor, with an IC50 in the low nanomolar range in NSCLC cell lines. Gem-miR-129 retains same nanomolar activity in both erlotinib- and osimertinib-resistant NSCLC cell lines. This potency is achieved through the dual mechanisms of the multi-targeted tumor suppressor miR-129, which suppresses HMGB1, YAP1, and PBX3, in conjunction with the expected therapeutic contribution of Gem following degradation of Gem-miR-129. A unique feature of Gem-miR-129 is its vehicle-free uptake in cultured NSCLC cells. Gem-miR-129 effectively inhibits NSCLC growth in a mouse model and significantly prolongs survival without overt toxicity under the tested conditions. Overall, Gem-miR-129 provides proof-of-concept for a novel tumor-suppressor miRNA-based therapeutic strategy for NSCLC and for overcoming TKI resistance.
Insights
A novel gemcitabine-modified microRNA (Gem-miR-129) effectively targets non-small cell lung cancer (NSCLC) and overcomes resistance to EGFR inhibitors. This approach shows potent efficacy in vitro and in vivo, offering a new therapeutic strategy for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Chemotherapy and tyrosine kinase inhibitor (TKI) resistance are primary causes of treatment failure in non-small cell lung cancer (NSCLC).
- Novel therapeutic strategies are urgently needed to overcome resistance mechanisms in NSCLC.
- MicroRNAs (miRNAs) offer potential as therapeutic agents due to their regulatory roles in cancer.
Purpose of the Study:
- To design and evaluate a novel, multi-targeted miRNA-based approach to overcome resistance to EGFR inhibitors in NSCLC.
- To investigate the therapeutic potential of gemcitabine-modified miR-129 (Gem-miR-129) in preclinical NSCLC models.
Main Methods:
- Modification of the tumor suppressor miR-129 by incorporating gemcitabine (Gem).
- Assessment of Gem-miR-129's efficacy and mechanism of action in vitro (NSCLC cell lines) and in vivo (mouse models).
- Evaluation of Gem-miR-129 activity in EGFR inhibitor-resistant NSCLC cell lines.
Main Results:
- Gem-miR-129 demonstrated potent inhibitory activity (low nanomolar IC50) in NSCLC cell lines, including resistant ones.
- The dual mechanism involves miR-129 targeting HMGB1, YAP1, and PBX3, plus gemcitabine's therapeutic effect.
- Gem-miR-129 exhibited vehicle-free uptake, inhibited tumor growth in vivo, and prolonged survival without significant toxicity.
Conclusions:
- Gem-miR-129 represents a novel tumor-suppressor miRNA-based therapeutic strategy for NSCLC.
- This approach shows promise for overcoming resistance to EGFR inhibitors and other TKIs.
- Gem-miR-129 provides a proof-of-concept for advanced miRNA-based cancer therapeutics.
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