Metabolic alterations driven by PFKFB3 upregulation confer resistance to trastuzumab in HER2-positive breast cancer - 09/01/26
Abstract |
Aims |
Resistance to anti-HER2 therapies, particularly trastuzumab, remains a major obstacle in the treatment of HER2-positive (HER2 +) breast cancer. This study aims to uncover novel mechanisms driving trastuzumab resistance with a focus on the immune component, key mediator of trastuzumab efficacy.
Methods |
We developed an isogenic cell line-derived xenograft model to perform transcriptome-wide analyses of trastuzumab-sensitive and -resistant tumors. To validate key findings, we employed a 3D cancer–immune co-culture system capable of quantifying antibody-dependent cellular cytotoxicity (ADCC).
Results |
Transcriptomic profiling revealed how trastuzumab treatment shifts tumor transcriptomes, including changes that remodel the metabolic landscape and distinct gene signatures associated with resistance, notably the upregulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Functional studies demonstrated that PFKFB3 promotes trastuzumab resistance by inducing metabolic rewiring and reducing ADCC. Silencing PFKFB3 restored immune-mediated cytotoxicity. Clinical dataset analyses confirmed that elevated PFKFB3 expression correlates with reduced overall and progression-free survival, and with incomplete pathological response to trastuzumab.
Conclusions |
PFKFB3 upregulation drives metabolic adaptations that confer resistance to trastuzumab in HER2 + breast cancer. These findings highlight PFKFB3 as a promising therapeutic target to overcome resistance and improve patient outcomes.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Highlights |
• | PFKFB3 upregulation promotes trastuzumab resistance in HER2 + breast cancer. |
• | Transcriptomic profiling reveals metabolic shifts linked to resistance. |
• | Silencing PFKFB3 restores ADCC and sensitizes cancer cells to trastuzumab. |
• | High PFKFB3 expression correlates with poor survival and treatment response. |
• | PFKFB3 is a potential therapeutic target to overcome trastuzumab resistance. |
Abbreviations : ADCC, CDX, DEG, ECAR, Erbb2/HER2, FDR, GSEA, GTEx, LFC, NK, OCR, OS, PCR, PFKFB3, PFS, RFS, RNAseq
Key words : HER2-targeting therapy, trastuzumab, ADCC, breast cancer, treatment resistance
Plan
Vol 194
Article 118898- janvier 2026 Retour au numéro
Article précédent
- Pharmacological characterization of the anti-nociceptive and anti-inflammatory effects of new CBD-based terpenyl-N-acyl-aryl-hydrazone analogues
- Carla Gabriely Gaião do Invêncio, Anna Carolina Pereira Lontra, João Pedro Barros de Paiva, Graziella dos Reis Rosa Franco, Isabela Marie Fernandes, Vanessa Silva Gontijo, Catarina Azevedo Ribeiro, Larissa do Nascimento dos Santos, Ana Clara Machado da Silva, Thaís Biondino Sardella Giorno, Sara Manuela Mendonça da Silva Cravo, Maria Emília Sousa, Claudio Viegas Jr., Patrícia Dias Fernandes
- Elucidation of mechanisms underlying the therapeutic effects of cordycepin on pulmonary hypertension, with a focus on cell senescence and gut microbiota
- Gaopeng Li, Zhixin Zhao, Mitsuhiro Machitani, Ryou Ishikawa, Kaori Ishikawa, Naoya Yokota, Reiji Haba, Kazufumi Nakamura, Zhihong Sun, Lin-Hai Kurahara, Katsuya Hirano
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?