EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for EGFR-mutant non-small cell lung cancer (NSCLC).
• Acquired drug resistance to EGFR TKIs is a significant clinical challenge in NSCLC treatment.
• HER3, a pseudokinase, is overexpressed in EGFR-mutant NSCLC and plays a role in resistance, despite lacking direct alterations.

Purpose of the Study:

• To evaluate the efficacy of HER3-DXd, a HER3-targeting antibody-drug conjugate (ADC), in EGFR TKI-resistant NSCLC models.
• To investigate a preclinical strategy to enhance HER3-DXd efficacy by combining it with osimertinib pretreatment.
• To explore the potential of a combination therapy for EGFR-mutant NSCLC.

Main Methods:

• Evaluation of HER3-DXd efficacy in patient-derived xenografts (PDXs) of EGFR inhibitor-resistant NSCLC.
• Assessment of HER3 membrane expression and HER3-DXd internalization following osimertinib pretreatment.
• Preclinical testing of the combination therapy comprising osimertinib and HER3-DXd.

Main Results:

• HER3-DXd demonstrated broad efficacy in HER3-expressing, EGFR TKI-resistant NSCLC xenografts.
• Osimertinib pretreatment increased HER3 membrane expression.
• The combination of osimertinib and HER3-DXd led to enhanced internalization and efficacy of HER3-DXd.

Conclusions:

• Targeting HER3 with HER3-DXd is a viable strategy for overcoming acquired resistance to EGFR TKIs in NSCLC.
• Combining osimertinib with HER3-DXd enhances HER3-DXd's internalization and efficacy, suggesting a promising therapeutic approach.
• The combination of osimertinib and HER3-DXd warrants clinical evaluation in patients with EGFR-mutant NSCLC.