HER2+ advanced gastric cancer: Current state and opportunities (Review)

Abstract

Human epidermal growth factor receptor 2 (HER2)⁺ gastric cancer (GC) is a distinct subtype of GC, accounting for 10‑20% of all cases of GC. Although the development of the anti‑HER2 monoclonal antibody trastuzumab has markedly improved response rates and prognosis of patients with HER2⁺ advanced GC (AGC), drug resistance remains a considerable challenge. Therefore, dynamic monitoring of HER2 expression levels can facilitate the identification of patients who may benefit from targeted therapy. Besides trastuzumab, DS‑8201 and RC48 have been applied in the treatment of HER2⁺ AGC, and several novel anti‑HER2 therapies are undergoing preclinical/clinical trials. At present, combination immunotherapy with anti‑HER2 agents is used as the first‑line treatment of this disease subtype. New promising approaches such as chimeric antigen receptor T‑cell immunotherapy and cancer vaccines are also being investigated for their potential to improve clinical outcomes. The current review provides new insights that will guide the future application of anti‑HER2 therapy by summarizing research progress on targeted therapy drugs for HER2⁺ AGC and combination treatments.

Keywords: advanced gastric cancer; human epidermal growth factor receptor 2; immunotherapy; targeted therapy; trastuzumab.

Figure 1

Activation process and mechanism of HER2 in tumor cells. In HER2⁺ GC, HER2 binds to ligands such as EGF which results in its activation, promoting its subsequent heterodimerization with other members of the HER family which enhances kinase activity. Activated HER2 phosphorylates several signaling molecules such as PI3K, AKT, RAS and RAF, to stimulate intracellular signal transduction thus enhances cancer progression. PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; mTOR, mammalian target of rapamycin; RAS, rat sarcoma viral oncogene homolog; RAF, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; MAPK, mitogen-activated protein kinase; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor.

Figure 2

Characteristics and mechanisms of action of different anti-HER2-targeted drugs. Anti-HER2-targeted drugs prevent HER2 activation by binding to different structural domains of HER2 heterodimers. PI3K, phosphoinositide-3 kinase; PKB, protein kinase B; mTOR, mechanistic target of rapamycin; MAPKK, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; HER, human epidermal growth factor receptor; MEK, mitogen-activated extracellular signal-regulated kinase; AKT, protein kinase B (PKB).

Figure 3

Characteristics of anti-HER2-targeted therapy combined with anti PD-1/PD-L1 immunotherapy. The activity of HER2 receptors is inhibited by anti-HER2-targeting drugs, which enhances the ability of immune cells to attack tumors. At the same time, anti-PD-1/PD-L1 immunotherapy can promote immune cell activity and alleviate tumor cell resistance to HER2-targeting drugs, exerting a synergistic antitumor effect. TCR, T-cell receptor; MHC, major histocompatibility complex; FcR, Fc Receptor; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; NK, natural killer; HER, human epidermal growth factor receptor; ADCC, antibody-dependent cell-mediated cytotoxicity.

Figure 4

CAR-T cell treatment principles and processes. CAR-T cell therapy uses genetically modified T cells to target and eliminate tumor cells. The treatment process involves collecting T cells, modifying them to express CARs, expanding and cultivating these engineered T cells, and ultimately administering them to patients to exert potent antitumor activity. CAR, chimeric antigen receptor; HER, human epidermal growth factor receptor.