Figure 1.

Main actionable signaling pathways in CCA. The signaling pathways involved in CCA progression and for which targeted agents are available, include receptor tyrosine kinases such as FGFR2 and ERBB and downstream signaling proteins, such as Janus kinases (JAK)/signal transducer and activator of transcription proteins (STAT), rat sarcoma virus (RAS)/Raf-1 proto-oncogene, serine/threonine kinase (RAF)/mitogen-activated extracellular signal-regulated kinases (ERK) kinase (MEK)/(ERK) and phosphatidylinositol 3-Kinase (PI3K). In addition, mutant IDH enzymes acquire the capacity to synthesize 2-HG from α-ketoglutarate (α-KG). 2-HG alters the activity of α-KG–dependent dioxygenase enzymes involved in cell differentiation, survival, and DNA methylation. HER2: human epidermal growth factor receptor 2; VEGFR: vascular endothelial growth factor receptor; MAPK: mitogen-activated protein kinase; AKT: serine/threonine-protein kinase; mTOR: mammalian target of rapamycin