# The Impact of HER3 Dynamics Altered by HER3-DXd Alone and in Combination with Driver Oncogene Inhibitors on HER3-DXd Efficacy

## TL;DR

This study explores how changes in HER3 dynamics affect the effectiveness of HER3-DXd, a cancer treatment, and suggests combining it with other drugs to improve results.

## Contribution

The study reveals that HER3 dynamics, not just baseline expression, influence HER3-DXd efficacy and supports combination therapies.

## Key findings

- Payload release from HER3-DXd correlates with baseline HER3 expression, internalization, and turnover rates.
- HER3 membrane levels in mice are affected by dose and dosing interval of HER3-DXd.
- Tyrosine kinase inhibitors increase HER3 expression, enhancing payload release in cancer cell models.

## Abstract

Targeted therapies have revolutionized treatment paradigms for a variety of cancer types; however, challenges including primary and acquired resistance persist, and there remains a high demand for novel treatment options. HER3 (ErbB3), a member of the human epidermal growth factor receptor family of receptor tyrosine kinases, is a target of HER3-DXd, an antibody–drug conjugate currently under clinical investigation. As was previously reported, the cytotoxic activity of HER3-DXd in preclinical models is primarily mediated by the antitumor activity of the released payload. Therefore, we investigated the impact of HER3 expression changes on payload release after HER3-DXd treatment using HER3-positive human cancer cell lines and their xenograft models. In vitro studies showed that the amount of payload released from cells after HER3-DXd treatment was associated with baseline HER3 expression levels, HER3 internalization rate, and turnover rate. In female CAnN.Cg-Foxn1nu/CrlCrlj mouse models, dose and dosing interval influenced membrane HER3 expression levels and tumor payload concentrations. Furthermore, membrane HER3 was upregulated by tyrosine kinase inhibitor treatment in non-small-cell lung cancer cell lines harboring specific driver mutations, including EGFR-activating mutations, ROS1 fusions, and ALK fusions. The increase in HER3 expression induced by osimertinib treatment was associated with increased payload release in PC-9 cells. Our results indicate that HER3 dynamics, as well as baseline HER3 expression, modulate payload release from HER3-DXd and support combination strategies to potentiate the antitumor activity of HER3-DXd.