Overview of current targeted therapy in gallbladder cancer

Abstract

Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1

Overview of GBC targeted sites and agents. Boxes highlight drugs undergoing clinical investigation as reviewed, with arrows indicating pathway/target activation and blocked lines indicating pathway/target inhibition. c-MET mesenchymal–epithelial transition factor, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, EGFR epidermal growth factor receptor, ERBB2 human epidermal growth factor 2, PD-1 programmed death-1, PD-L1 programmed death ligand 1, PI3K phosphoinositide 3-kinase, AKT protein kinase B, also known as PKB, mTOR mammalian target of rapamycin, MEK mitogen-activated protein kinase, ERK extracellular signal-regulated kinase

Fig. 2

Summary of HER2 mutations in the COSMIC database (a) and mutation information of HER2 in our previous two studies (b)

Fig. 3

Immunoregulation of PD-L1/PD-1 in GBC. a Activated ERBB2/ERBB3 mutations upregulate PD-L1 expression through activation of the PI3K/AKT signaling and RAS/RAF/MEK/ERK pathway to induce immune evasion of GBC cells. b Yellow boxes highlight that drug targeted ERBB2, PD-1, or PD-L1 could dampen immune evasion of GBC cells

Fig. 4

Schematic of the clinical trial in our center (NCT03768375). Based on genomic and proteomic profiling of participants, patients received personalized targeted drugs with FOLFRINOX treatment or just FOLFRINOX treatment