Resistance mechanisms to HER2-targeted therapy in gastroesophageal adenocarcinoma: A systematic review
Dionne Blangé1, Charlotte I Stroes1, Sarah Derks2
1Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, The Netherlands.
Introduction:
Despite promising results following targeted treatment with human epidermal growth factor receptor 2 (HER2)-inhibitors in HER2-positive gastric and esophageal adenocarcinoma (GEA), prognosis remains dismal. Many patients ultimately demonstrate progression following treatment due to resistance to HER2-targeted therapy. Here, we describe the potential primary and secondary resistance mechanisms to HER2-targeted therapy in GEA.
Methods:
We systematically searched PubMed/MEDLINE, EMBASE, and CENTRAL for eligible studies describing changes that were associated with drug resistance. Study quality was assessed using an adjusted version of the OHAT risk of bias tool. Quality of proposed resistance mechanisms was assessed using predefined criteria.
Results:
In total, 913 records were screened, of which 73 were included that investigated mechanisms of resistance against anti-HER2 treatment in cell lines, xenograft models, patient tissue samples, and publicly available datasets. HER2-targeted therapy resistance was found to be caused by HER2 receptor changes, upregulation of compensatory receptors, (re)activation of downstream signaling pathways like PI3K/AKT and MAPK, epithelial-to-mesenchymal transition, acquirement of stem cell-like properties, alterations in cell cycle related genes, cellular metabolism, and drug pharmacokinetics.
Discussion:
Several different mechanisms can contribute to drug resistance to anti-HER2 treatment in GEA, mainly through loss of or mutations in the HER2 receptor and upregulation of alternative receptors such as MET, HER3, and FGFRs. Despite these preclinical results, methods to overcome the proposed resistance mechanisms in the clinical setting are lacking. Therefore, further investigation of therapy resistance in GEA patients treated with HER2 targeted therapy is essential to overcome resistance and improve treatment outcome of these patients.
Insights
Resistance to human epidermal growth factor receptor 2 (HER2)-inhibitors in HER2-positive gastric and esophageal adenocarcinoma (GEA) is driven by HER2 receptor alterations and compensatory signaling pathways. Overcoming this resistance requires further clinical investigation to improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Targeted therapy with human epidermal growth factor receptor 2 (HER2)-inhibitors shows promise in HER2-positive gastric and esophageal adenocarcinoma (GEA).
- However, patient prognosis remains poor due to acquired resistance to HER2-targeted therapy.
- Understanding resistance mechanisms is crucial for improving treatment efficacy.
Purpose of the Study:
- To systematically review and describe primary and secondary resistance mechanisms to HER2-targeted therapy in GEA.
- To identify key molecular and cellular alterations contributing to treatment failure.
Main Methods:
- A systematic literature search was conducted across PubMed/MEDLINE, EMBASE, and CENTRAL databases.
- Eligible studies investigating resistance mechanisms were included and assessed for quality.
- Predefined criteria were used to evaluate the quality of proposed resistance mechanisms.
Main Results:
- 73 studies investigating resistance mechanisms in cell lines, xenografts, patient samples, and datasets were included.
- Resistance mechanisms involve HER2 receptor changes, compensatory receptor upregulation (MET, HER3, FGFRs), PI3K/AKT and MAPK pathway reactivation, epithelial-to-mesenchymal transition, stem cell properties, cell cycle alterations, metabolism changes, and pharmacokinetics.
- Loss of or mutations in the HER2 receptor are key contributors.
Conclusions:
- Multiple mechanisms, including HER2 alterations and compensatory signaling, drive resistance to anti-HER2 therapy in GEA.
- Current clinical strategies to overcome these resistance mechanisms are lacking.
- Further research into therapy resistance in GEA is essential to improve patient treatment outcomes.
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