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Updated: Sep 1, 2025
Development of Compendium for Esophageal Squamous Cell Carcinoma
Published on: April 12, 2024
Targeting the complexity of ERBB2 biology in gastroesophageal carcinoma
J E Augustin1, P Soussan2, A J Bass3
1Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, USA; Department of Pathology, Henri Mondor University Hospital, Assistance Publique - Hôpitaux de Paris, Créteil, France; INSERM U955 Team 18, Université Paris Est Créteil - Faculté de Médecine, Créteil, France.
Abstract:
ERBB2 is the most prominent therapeutic target in gastroesophageal adenocarcinoma (GEA). For two decades, trastuzumab was the only treatment available for GEA overexpressing ERBB2. Several drugs showing evidence of efficacy over or in complement to trastuzumab in breast cancer failed to show clinical benefit in GEA. This resistance to anti-ERBB2 therapy is peculiarly recurrent in GEA and is mostly due to tumor heterogeneity with the existence of low expressing ERBB2 tumor clones and loss of ERBB2 over time. The development of new ERBB2 testing strategies and the use of antibody-drug conjugates having a bystander effect are providing new tools to fight heterogeneity in ERBB2-positive GEA. Co-amplifications of tyrosine kinase receptors, alterations in mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways and in proteins controlling cell cycle are well known to contribute resistance to anti-ERBB2 therapy, and they can be targeted by dual therapy. Recently described, NF1 mutations are responsible for Ras phosphorylation and activation and can also be targeted by MEK/ERK inhibition along with anti-ERBB2 therapy. Multiple lines of evidence suggest that immune mechanisms involving antibody-dependent cell-mediated cytotoxicity are preponderant over intracellular signaling in anti-ERBB2 therapy action. A better comprehension of these mechanisms could leverage immune action of anti-ERBB2 therapy and elucidate efficacy of combinations associating immunotherapy and anti-ERBB2 therapy, as suggested by the recent intermediate positive results of the KEYNOTE-811 trial.
Insights
ERBB2-positive gastroesophageal adenocarcinoma (GEA) shows resistance to anti-ERBB2 therapy due to tumor heterogeneity. New strategies like antibody-drug conjugates and dual therapies targeting resistance mechanisms offer improved treatment options for GEA patients.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2) is a key therapeutic target in gastroesophageal adenocarcinoma (GEA).
- Trastuzumab has been the sole anti-ERBB2 therapy for GEA for 20 years, with limited success in overcoming resistance.
- Tumor heterogeneity, including low ERBB2-expressing clones and ERBB2 loss, contributes significantly to therapeutic resistance in GEA.
Purpose of the Study:
- To review the challenges and advancements in anti-ERBB2 therapy for ERBB2-positive GEA.
- To explore novel therapeutic strategies and resistance mechanisms in GEA.
- To highlight the role of tumor heterogeneity and immune mechanisms in anti-ERBB2 treatment efficacy.
Main Methods:
- Literature review of studies on ERBB2-targeted therapies in GEA.
- Analysis of resistance mechanisms, including genetic alterations and signaling pathways.
- Examination of emerging therapeutic strategies like antibody-drug conjugates and immunotherapy combinations.
Main Results:
- Resistance to anti-ERBB2 therapy in GEA is driven by tumor heterogeneity and alterations in MAPK and PI3K pathways.
- NF1 mutations activate Ras signaling, presenting a target for MEK/ERK inhibition combined with anti-ERBB2 therapy.
- Antibody-dependent cell-mediated cytotoxicity plays a crucial role in anti-ERBB2 therapy, suggesting potential for immunotherapy combinations.
Conclusions:
- New ERBB2 testing strategies and antibody-drug conjugates with bystander effects are emerging to combat GEA heterogeneity.
- Targeting co-amplifications, MAPK/PI3K pathways, and NF1 mutations offers potential for dual therapy in GEA.
- Understanding immune mechanisms can optimize anti-ERBB2 therapy and combination strategies, as indicated by trials like KEYNOTE-811.
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