Targeting HER3 with EZN-3920: Modulating PI3K/Akt Pathway and Enhancing Gefitinib's Antiproliferative Activity in Tumor Cells

The ErbB family is comprised of four receptors, including ErbB1, HER2, HER3, and HER4. HER3 has been identified as a potential target for antitumor therapies due to its role in heterodimerization with other receptors, its significance in the PI3K signaling pathway, and its activation in cells resistant to other ErbB inhibitors. This research focused on the evaluation of EZN3920, an antisense oligonucleotide designed to target HER3 mRNA.

In the experimental phase, EZN3920's impact on HER3 mRNA and protein levels, as well as its downstream effects on the PI3K/Akt pathway, was assessed. The study utilized various cancer cell lines and examined the compound's efficacy in reducing HER3 expression, inhibiting phospho-Akt levels, and inducing apoptosis. The combination of EZN3920 with the EGFR inhibitor gefitinib was also explored to assess its synergistic antiproliferative effects.

In vitro testing revealed that EZN3920 effectively reduced HER3 mRNA and protein levels with a low IC50 value, leading to a decrease in phospho-Akt levels and cell growth inhibition. The compound also induced apoptosis, as indicated by increased caspase 3/7 activities. The knockdown of HER3 by EZN3920 was found to enhance the effectiveness of gefitinib in both sensitive and resistant cancer cells.

In vivo studies conducted on nude mice xenograft models demonstrated that EZN3920 could achieve up to 95% inhibition of ErbB3 mRNA in the liver following systemic administration. Furthermore, the compound significantly reduced HER3 mRNA and protein expression in tumors, along with the downstream p-Akt levels.

The study concludes that EZN3920 is a potent and specific inhibitor of HER3 expression, capable of inhibiting the PI3K/Akt pathway both in vitro and in vivo. The compound also enhances the activity of gefitinib in resistant tumor cells, suggesting its potential as a therapeutic agent for ErbB-driven cancers. The research also indicates that further investigation into combining EZN3920 with other biological agents to overcome resistance to ErbB inhibitors is warranted.