# YAP inhibition overcomes adaptive resistance in HER2-positive gastric cancer treated with trastuzumab via the AKT/mTOR and ERK/mTOR axis

## TL;DR

This study shows that inhibiting YAP can help overcome resistance to trastuzumab in HER2-positive gastric cancer by targeting specific signaling pathways.

## Contribution

The study identifies YAP reactivation as a mechanism of trastuzumab resistance and proposes YAP inhibition as a novel therapeutic strategy.

## Key findings

- Trastuzumab resistance in HER2-positive GC is linked to YAP gene reactivation.
- YAP inhibition combined with trastuzumab shows synergistic effects via AKT/mTOR and ERK/mTOR pathways.
- Chromatin remodeling is triggered by long-term trastuzumab treatment, leading to YAP transcription.

## Abstract

Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a heterogeneous GC subtype characterized by the overexpression of HER2. To date, few specific targeted therapies have demonstrated durable efficacy in HER2-positive GC patients, with resistance to trastuzumab typically emerging within 1 year. However, the mechanisms of resistance to trastuzumab remain incompletely understood, presenting a significant challenge to clinical practice.

In this study, we integrated genetic screening and bulk transcriptome and epigenomic profiling to define the mechanisms mediating adaptive resistance to HER2 inhibitors and identify potential effective therapeutic strategies for treating HER2-positive GCs.

We revealed a potential association between adaptive resistance to trastuzumab in HER2-positive GC and the expression of YES-associated protein (YAP). Notably, our investigation revealed that long-term administration of trastuzumab triggers extensive chromatin remodeling and initiates YAP gene transcription in HER2-positive cells characterized by the initial inhibition and subsequent reactivation. Furthermore, treatment of HER2-positive GC cells and cell line-derived xenografts (CDX) models with YAP inhibitors in combination with trastuzumab was found to induce synergistic effects through the AKT/mTOR and ERK/mTOR pathways.

These findings underscore the pivotal role of reactivated YAP and mTOR signaling pathways in the development of adaptive resistance to trastuzumab and may serve as a promising joint target to overcome resistance to trastuzumab.

The online version contains supplementary material available at 10.1007/s10120-024-01508-3.