Hepatocellular carcinoma (KEGG map)
This KEGG map shows how hepatitis viruses, alcohol and aflatoxin leave the liver with mutations in telomerase, TP53, Wnt/beta-catenin, PI3K/AKT/mTOR and the oxidative stress sensor NRF2, which together drive liver cancer. It matters because the map explains why liver cancer is treated mainly with angiogenesis blockers and immunotherapy rather than a single targeted drug.
Overview
Hepatocellular carcinoma (HCC) is the major primary liver cancer and one of the few human tumours with a viral aetiology. KEGG map hsa05225 draws the genetic and epigenetic changes that follow HBV or HCV infection and alcohol or aflatoxin B1 exposure. Recurrently mutated genes cluster in several driver processes: telomere maintenance (TERT promoter mutation and over-expression), TP53, cell cycle control (CDKN2A deletion, RB1 loss), Wnt/beta-catenin (activating CTNNB1 mutation, AXIN1 inactivation, FZD7 over-expression), PI3K/AKT/mTOR (PIK3CA mutation, PTEN loss), receptor signalling through MET/HGF, IGF2/IGF1R and TGF-alpha/EGFR into RAS-ERK and PLC-gamma/PKC, reduced TGF-beta receptor II, and, from exome sequencing, chromatin remodelling (ARID1A, ARID2) and the oxidative stress pathway (KEAP1 loss or NFE2L2/NRF2 activation).
Llovet and colleagues, Nature Reviews Disease Primers, 2021 (doi:10.1038/s41572-020-00240-3) review the disease: TERT promoter, CTNNB1 and TP53 are the most frequent mutations, none of the main drivers is directly druggable, and CTNNB1-mutant tumours are immune-excluded and respond poorly to checkpoint inhibitors, while MET-high and VEGF-driven tumours underpin the success of multikinase and anti-angiogenic drugs.
What drugs do about it: first-line systemic therapy is atezolizumab plus bevacizumab (PD-L1 plus VEGF) or durvalumab plus tremelimumab (PD-L1 plus CTLA-4), with the multikinase inhibitors sorafenib and lenvatinib (both listed by KEGG) as alternatives; regorafenib, cabozantinib (which also hits MET) and ramucirumab (for high AFP) are used after progression. In China camrelizumab plus rivoceranib and donafenib are approved. Glypican-3, a proteoglycan over-expressed on most HCC, is an antigen for antibodies and CAR-T cells in trials. The Wnt/beta-catenin and TERT steps remain undrugged.
In one picture
A factory that has been running in a toxic, inflamed environment for decades. The chronic damage rewrites several control panels at once: the age counter is disabled (TERT), the emergency stop is cut (TP53), the growth dial is stuck (Wnt, PI3K) and the smoke alarm is disconnected (NRF2). No single repair fixes it, so treatment cuts the blood supply and calls in the immune system.
Diagram
top- First line: atezolizumab plus bevacizumab (PD-L1 plus VEGF) or durvalumab plus tremelimumab (PD-L1 plus CTLA-4)
- Multikinase inhibitors sorafenib and lenvatinib (listed by KEGG), and camrelizumab plus rivoceranib or donafenib in China
- Second line: regorafenib, cabozantinib (also blocks MET), ramucirumab for AFP-high disease
- Glypican-3 directed antibodies and CAR-T cells in clinical trials
- Wnt/beta-catenin and TERT steps: no approved drug yet
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