HER2, the key to revolutionizing cancer treatment

Oncology

#Oncology #Cancer #HER2 #TargetedTherapy #TherapeuticInnovation

HER2 (human epidermal growth factor receptor 2) is a transmembrane receptor involved in the regulation of cell growth and intracellular signaling. Its role is critical in several types of cancer, such as breast, gastric, bladder, and non-small cell lung cancer (NSCLC), where it is frequently altered. These alterations result from genetic mutations, HER2 gene amplifications, or overexpression on the surface of tumor cells. They lead to abnormal activation of signaling pathways, promoting uncontrolled cell proliferation, tumor cell survival, and resistance to conventional treatments.

Understanding the molecular mechanisms involving HER2 has paved the way for significant advances in the development of targeted therapies: monoclonal antibodies, tyrosine kinase inhibitors (TKI), antibody-drug conjugates (ADC), ... Designed to block HER2 or limit its carcinogenic effects, these approaches have revolutionized the management of HER2-positive cancers. This review explores the efficacy of these treatments on different solid tumors. New combinations have also been studied to overcome current challenges such as resistance.

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HER2, the key to more effective treatment?

HER2 mutations lead to amplification or overexpression of this protein, activating signaling pathways like PI3K/AKT and MAPK. These mechanisms promote uncontrolled proliferation of tumor cells. HER2-positive cancers are thus associated with a particularly poor prognosis, with a high risk of metastases, which complicates the management.

Anti-HER2 monoclonal antibodies have revolutionized the treatment of HER2-positive cancers. Trastuzumab marked a turning point. When combined with pertuzumab (CLEOPATRA trial), it significantly improves overall survival in patients with metastatic forms. The association with bispecific antibodies (W25) targets simultaneously multiple domains of HER2, enhancing their efficacy. Combined with chemotherapy or immunotherapy (KEYNOTE-811 and ToGA trials), trastuzumab is particularly effective in the treatment of HER2-positive gastric cancers.

TKIs represent another major advancement. Among these molecules, lapatinib has shown efficacy, especially when combined with aromatase inhibitors. New TKIs, such as tucatinib or pyrotinib, also offer valuable alternatives. Additionally, molecules like poziotinib and pyrotinib expand the perspectives in NSCLC with HER2 mutations.

ADCs, by combining an HER2-targeting antibody with a cytotoxic agent, allow precise destruction of tumor cells. T-DM1 and T-DXd have become major therapeutic options in the treatment of breast, gastric, and NSCLC cancers. These ADCs show particular efficacy, even in patients with low HER2 expression (Destiny-Breast04 and Destiny-Gastric01 trials). T-DXd, in particular, has demonstrated significant improvements in overall survival, offering new perspectives for patients previously considered to have a poor prognosis.

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HER2: towards a new therapeutic era

HER2-positive cancer is an aggressive form of tumor, characterized by HER2 protein overexpression. This cancer subtype represents a major clinical challenge, due to its rapid progression and impact on patient prognosis. Despite advances in targeted treatments, therapeutic resistance and side effects still limit the effectiveness of current approaches.

This review aimed to explore innovations in HER2-targeted therapies, focusing on bispecific antibodies, next-generation ADCs, and combination therapies. Strategies to overcome resistance and improve diagnosis were also examined.

Targeted HER2 therapies have significantly improved survival rates in patients with HER2-positive cancers. The progress achieved, particularly with ADCs and combination treatments, offers new options for patients with advanced or resistant cancers. However, treatment resistance and the complexity of diagnostic tests remain major obstacles to optimal management.
The development of more targeted and personalized approaches, such as bispecific antibodies and therapeutic combinations, is a major challenge. The use of liquid biopsies to detect HER2 status could also transform diagnosis and patient monitoring. By pursuing innovations and clinical trials, HER2-targeted therapies could continue to revolutionize the treatment of advanced cancers and offer renewed hope for patients.

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Source(s) :
Zhu, K., et al. (2024). HER2-targeted therapies in cancer: a systematic review. Biomarker Research, 12(1), 16 ;

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