# Colorectal cancer (KEGG map)

Source: https://onco.cc/pathways/colorectal-cancer-signalling/  
OnCo record `colorectal-cancer-signalling` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

This KEGG map traces the step-by-step genetic route from normal bowel lining to colorectal cancer: APC loss unleashes Wnt, KRAS mutation drives growth, then TP53 and TGF-beta/SMAD4 loss remove the last brakes, or alternatively mismatch repair fails and mutations pile up. Knowing which route a tumour took decides which drugs work.

## Summary

Colorectal cancer arises from the colorectal epithelium through accumulated alterations in defined oncogenes and tumour suppressors. KEGG map hsa05210 draws two mechanisms of genomic instability. The chromosomal instability (CIN) route follows the classical adenoma to carcinoma sequence: inactivation of APC (germline in familial adenomatous polyposis) or activating mutation of CTNNB1 stabilises beta-catenin and switches on Wnt target genes (MYC, cyclin D1); activating KRAS mutation, or over-expression of EGFR and its ligands (EGF, TGF-alpha, amphiregulin, epiregulin), drives RAS-ERK and PI3K-AKT signalling; then loss of TP53, of SMAD4 and DCC on chromosome 18q, and of TGF-beta receptor II removes growth arrest and apoptosis. The microsatellite instability (MSI) route follows inactivation of the mismatch repair genes MLH1 (usually by promoter hypermethylation) or MSH2 (germline in Lynch syndrome, HNPCC), with secondary frameshift mutations in genes carrying coding microsatellites such as TGFBR2 and BAX.

Dekker and colleagues, The Lancet, 2019 (doi:10.1016/S0140-6736(19)32319-0) place these routes in the clinic: KRAS, NRAS and BRAF status decides whether anti-EGFR antibodies can be used, MSI status decides whether immune checkpoint inhibitors are appropriate, and the consensus molecular subtypes separate MSI-immune, canonical Wnt, metabolic and mesenchymal TGF-beta-driven tumours.

What drugs do about it: anti-EGFR antibodies (cetuximab, panitumumab) block the receptor layer in RAS wild-type, left-sided tumours; encorafenib plus cetuximab treats BRAF V600E disease; KRAS G12C inhibitors (sotorasib, adagrasib) combined with anti-EGFR treat the G12C subset; pembrolizumab, nivolumab and ipilimumab treat MSI-high tumours; bevacizumab, ramucirumab, regorafenib and fruquintinib block VEGF-driven angiogenesis; HER2-directed therapy (trastuzumab with tucatinib, trastuzumab deruxtecan) treats HER2-amplified tumours. No approved drug yet targets the APC/Wnt step itself.

## Fields

- Kind: Pathway
- Last checked: 2026-09-10
- Also known as: KEGG hsa05210; Colorectal cancer
- Analogy: A car with several independent brakes and an accelerator. APC loss removes the handbrake (Wnt runs), KRAS jams the accelerator, TP53 and SMAD4 loss cut the foot brakes. In the MSI route the mechanic who proofreads the repair manual (mismatch repair) is sacked, so faults accumulate everywhere at once, which oddly makes the car more visible to the immune system's traffic police.
- Interventions: Anti-EGFR antibodies (cetuximab, panitumumab) for RAS wild-type, BRAF wild-type, left-sided tumours; Encorafenib plus cetuximab for BRAF V600E colorectal cancer; KRAS G12C inhibitors (sotorasib, adagrasib) combined with anti-EGFR antibodies for the G12C subset; Immune checkpoint inhibitors (pembrolizumab, nivolumab plus ipilimumab) for mismatch repair deficient, MSI-high tumours; Anti-angiogenics (bevacizumab, ramucirumab, regorafenib, fruquintinib) and HER2-directed therapy (trastuzumab with tucatinib, trastuzumab deruxtecan) for HER2-amplified disease; Wnt/APC step: no approved drug yet

## Sources

- KEGG map hsa05210: https://www.kegg.jp/pathway/hsa05210
- Review: Colorectal cancer (Lancet seminar): https://doi.org/10.1016/S0140-6736(19)32319-0

## Connected records

- pathways: [Intrinsic apoptosis (BCL-2 family)](https://onco.cc/pathways/apoptosis-bcl2/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/), [VEGF angiogenesis](https://onco.cc/pathways/vegf-angiogenesis/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- cancers: [BRAF V600E-mutant colorectal cancer](https://onco.cc/cancers/braf-v600e-colorectal/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Early-onset colorectal cancer (under 50)](https://onco.cc/cancers/early-onset-colorectal/), [HER2-amplified colorectal cancer](https://onco.cc/cancers/her2-amplified-colorectal/), [KRAS G12C-mutant colorectal cancer](https://onco.cc/cancers/kras-g12c-colorectal/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/), [Rectal cancer](https://onco.cc/cancers/rectal-cancer/)
- targets: [APC](https://onco.cc/targets/apc/), [BRAF](https://onco.cc/targets/braf/), [DCC](https://onco.cc/targets/dcc/), [EGFR](https://onco.cc/targets/egfr/), [HER2](https://onco.cc/targets/her2/), [KRAS](https://onco.cc/targets/kras/), [MLH1](https://onco.cc/targets/mlh1/), [MSH2](https://onco.cc/targets/msh2/), [NRAS](https://onco.cc/targets/nras/), [PD-1](https://onco.cc/targets/pd1/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [SMAD4](https://onco.cc/targets/smad4/), [TP53](https://onco.cc/targets/tp53/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Fruquintinib](https://onco.cc/drugs/fruquintinib/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Panitumumab](https://onco.cc/drugs/panitumumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Regorafenib](https://onco.cc/drugs/regorafenib/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Trifluridine/tipiracil](https://onco.cc/drugs/trifluridine-tipiracil/), [Tucatinib](https://onco.cc/drugs/tucatinib/)
- key papers: [A genetic model for colorectal tumorigenesis](https://onco.cc/key-papers/paper-fearon-cell/), [Clinical sequencing defines the genomic landscape of metastatic colorectal cancer](https://onco.cc/key-papers/paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018/), [Colorectal cancer](https://onco.cc/key-papers/paper-dekker-lancet/), [Comprehensive molecular characterization of human colon and rectal cancer](https://onco.cc/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/), [Genetic alterations during colorectal-tumor development](https://onco.cc/key-papers/paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988/)

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