Advances in targeted therapy for esophageal cancer

Abstract

Esophageal cancer (EC) is one of the most lethal cancers in the world, and its morbidity and mortality rates rank among the top ten in China. Currently, surgical resection, radiotherapy and chemotherapy are the primary clinical treatments for esophageal cancer. However, outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional treatments. As a new type of approach, targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer; these include cetuximab and bevacizumab, which target epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), respectively. In addition, other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously developed. For example, trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), has been approved by the Food and Drug Administration (FDA) as a first-line treatment of HER-2-positive cancer. Moreover, the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma (ESCC). These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer patients. Nevertheless, adverse events, optimal dosages and effective combinations still need further investigation. In this review, we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs, discuss their efficacy and safety, and provide a clinical rationale for precision medicine in esophageal cancer.

Fig. 1

The most studied targets and related drugs in esophageal cancer. The drugs in red text have been approved by the FDA for the treatment of esophageal cancer, and the remaining drugs in black text are still in different stages of research. EGF epidermal growth factor, EGFR epidermal growth factor receptor, HER2 human epidermal growth factor receptor 2, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, CTLA-4 cytotoxic T-lymphocyte-associated antigen 4, PD-1 programmed death receptor 1, PD-L1 programmed death-ligand 1, HGF hepatocyte growth factor, c-MET c-mesenchymal-epithelial transition

Fig. 2

EGFR-related, VEGFR-related, HER2-related, and c-MET-related signaling pathways. These receptors on the cell membrane are activated by binding to the corresponding ligands (therapeutic drugs), which lead to autophosphorylation of tyrosine residues. The signaling pathways include the PI3K/AKT/mTOR, Src/FAK, Ras/Raf/MEK/ERK, Ras/MEKK-1/MKK-7/JNK, and PLC-γ/PKC pathways. By regulating these pathways, targeted drugs can ultimately affect the survival, adhesion, proliferation, angiogenesis, movement, and invasion of cancer cells

Fig. 3

Mechanism of anti-programmed death 1 (PD-1) receptor-programmed and anti-programmed death-ligand 1 (PD-L1) inhibitor-mediated cancer immunotherapy. a When PD-1 binds to PD-L1, the immune effect of T cells is suppressed, leading to immune escape. b The therapeutic antibodies (anti-PD-1 and anti-PD-L1) bind to PD-1 and PD-L1, respectively, blocking the interaction of PD-1 and PD-L1 and releasing the immunosuppression of T cells. Subsequently, cancer cell lysis will occur

Fig. 4

The mechanism of CTLA-4 immune checkpoint blockade by therapeutic antibodies employed in cancer immunotherapy. a CTLA-4 on T cells competes with CD28 to bind to B7 ligands on APCs (antigen-presenting cells). Once CTLA-4 binds to B7, the activity of T cells will be suppressed, and immune escape can occur. b After anti-CTLA-4 binds CTLA-4, CD28 will bind to B7, which then activates the T cell and ultimately leads to the death of the cancer cells