Pertuzumab Enhances the Antitumor Activity of T-DXd in HER2-Positive Gastric Cancer Cells

Sep 22, 2026

Pertuzumab enhances the antitumor activity of trastuzumab deruxtecan (T-DXd) in HER2-positive gastric cancer cells by addressing HER2–HER3 signaling. Preclinical in vitro and in vivo data evaluate T-DXd efficacy across HER2-expressing cell lines, show that high membrane HER2 expression predicts response, and identify synergy between pertuzumab and T-DXd in specific HER2–HER3 dimer contexts. NRG1 stimulation attenuates T-DXd effects, with partial reversal by pertuzumab in NCI-N87 but not OE19.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

HER2 amplification and HER2-targeted therapy background

Trastuzumab deruxtecan (T-DXd) design and clinical rationale

Pertuzumab Enhances the Antitumor Activity of T-DXd in HER2-Positive Gastric Cancer Cells Minsu Kang1,2, Kui-Jin Kim3, Hyeon Jeong Oh4, Ji Hea Sung2, Milang Nam2, Bo-Ram Park2, Sung-Hyun Hwang3, Eun Hee Jung2, Koung Jin Suh2, Ji-Won Kim2, Se Hyun Kim2, Jin Won Kim2, Yu Jung Kim2, Jee Hyun Kim2, and Keun-Wook Lee1,2 | | | A | | B | S | | T | R | | A | | C | T | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | For HER2-positive advanced gastric cancer, a recent major therapeutic advancement is the development of trastuzumab deruxtecan (T-DXd), a HER2-directed antibody–drug conjugate. In this disease, simultaneously targeting HER2 and HER3 pathways has the potential to be a promising therapeutic strategy. However, the therapeutic approach of combining T-DXd with pertuzumab, which disrupts HER2–HER3 heterodimerization, has not yet been explored in gastric cancer, making this study a pioneering effort. In vitro, T-DXd efficacy correlated with high levels of membrane HER2 expression. Among the 12 cell lines tested, two cell lines (NCI-N87 and OE19) confirmed as HER2 3+ by IHC showed the most effective proliferation inhibition by T-DXd. When comparing NCI-N87 and OE19, HER2– HER3 dimerization was found to be more abundant in NCI-N87, and combination treatment with pertuzumab and T-DXd showed synergy
􀀶 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | in cell growth inhibition in NCI-N87 but not in OE19. NRG1 stimulation attenuated the antiproliferative effect of T-DXd. This attenuation ofT-DXd activity by NRG1 was partially reversed by the addition ofpertuzumab in NCI-N87 but not in OE19. Notably, the combination of T-DXd and pertuzumab enhanced membrane HER2 internalization more effectively in NCI-N87 than in OE19. In vivo mouse experiments using NCI-N87 cells showed the combination treatment significantly suppressed tumor growth compared with either monotherapy. Taken together, our findings suggest that dual targeting of HER2 and HER3 with T-DXd and pertuzumab may improve therapeutic outcomes in HER2-positive gastric cancer, particularly in tumors enriched with HER2–HER3 heterodimers. These preclinical data provide strong rationale for clinical trials evaluating this combination strategy in HER2-positive gastric cancer. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Introduction Gastric cancer is a serious global health challenge and is the fifth most common malignancy and the fourth leading cause of cancerrelated deaths worldwide (1). HER2 amplification is a key molecular characteristic of a subset of gastric cancer cases, constituting 7% to 34% of all gastric adenocarcinomas (2) . The introduction of HER2-targeted therapies, particularly the mAb trastuzumab, in combination with chemotherapy, has improved patient survival (2) . Trastuzumab deruxtecan (T-DXd), an innovative antibody–drug conjugate (ADC), marks a significant advancement in HER2-positive gastric cancer therapy. By linking trastuzumab to topoisomerase 1 (T

FAQs

What therapeutic rationale supports combining T-DXd with pertuzumab in HER2-positive gastric cancer?

The study targets both HER2 and HER3 pathways, aiming to disrupt HER2–HER3 heterodimerization while leveraging T-DXd’s HER2-selective delivery of a cytotoxic payload.

How does HER2 expression relate to T-DXd efficacy in the tested cell lines?

In vitro results indicate that T-DXd efficacy correlates with high levels of membrane HER2 expression, and the most effective proliferation inhibition is observed in HER2 3+ lines such as NCI-N87 and OE19.

What is the impact of NRG1 stimulation and how does pertuzumab modify it?

NRG1 stimulation attenuates the antiproliferative effect of T-DXd; this attenuation is partially reversed by adding pertuzumab in NCI-N87 but not in OE19.

Sep 22, 2026

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