Cancer / Oncology/KRAS-mutant colorectal cancer
Gastrointestinal · subtype
KRAS-mutant colorectal cancer
Subtype of Colorectal cancer
Clinical / Scientific
KRAS mutation activates downstream of EGFR, predicting lack of benefit from anti-EGFR antibodies. Direct KRAS targeting is evolving and allele-specific.
Core Biological Drivers
KRAS
GTPase lock bypassing EGFR.
Key Pathways
Scientific explanation
RAS GTPases and RAF kinases are frequent oncogenic nodes. KRAS, NRAS and BRAF mutations lock mitogenic signalling on in a ligand-independent way in many tumours.
Scientific explanation
The RAS–RAF–MEK–ERK cascade transmits mitogenic RTK signals to programmes for proliferation and differentiation.
Scientific explanation
phosphorylates PIP2 to PIP3, recruiting . supports growth, survival, glucose uptake and mTORC1 input. Pathway activation is common via PIK3CA mutation, PTEN loss or -tyrosine- signalling.
Scientific explanation
Canonical Wnt signalling stabilizes β-catenin, driving TCF/LEF . APC loss is a classic colorectal initiating event; the pathway also contributes to stemness in several tissues.
Scientific explanation
Aerobic (Warburg metabolism) supports ATP, biomass and redox buffering even when oxygen is available. Hexokinase, PKM2 and lactate export are frequent nodes.
Pathway Convergence
Target → pathway → downstream effect → biological consequence. Shared intersections are mechanistic maps, not protocols.
Growth-factor signalling
Ligand or mutation-driven RTK input feeds PI3K/AKT and mTORC1, supporting anabolic growth. This is a map of signalling, not a treatment protocol.
Energy stress
Energetic stress activates AMPK, which can restrain mTORC1. Biguanides and related tools map onto this axis in models.
Metabolic Vulnerabilities
Aerobic supports ATP, biomass and acidification even when oxygen is available. Extent varies by tumour and remains a vulnerability hypothesis rather than a uniform target.
Glutamine anaplerosis and nucleotide nitrogen demand are prominent in MYC-high and rapidly proliferating tumours. Dependence is heterogeneous.
Tumor Microenvironment
Tumour-associated macrophages and myeloid-derived suppressor cells secrete cytokines that support invasion and blunt cytotoxic T cells.
Metastasis Module
, protease-mediated invasion, , circulating tumour-cell survival and organ-specific colonization form the metastatic cascade. Pre-metastatic niches and vascular permeability influence tropism.
Resistance Biology
reactivation and allele-specific escape.
Cancer Stemness
Wnt, Notch, Hedgehog, ALDH and CD44-associated programmes can mark stem-like fractions with quiescence and therapy tolerance. These markers are not interchangeable across tumour types.
Mechanism-Based Adjunctive Strategies
Compounds appear only where a mechanistic overlap exists for this cancer. Evidence tiers are not equivalent. Nothing here is a treatment recommendation.
Statins (HMG-CoA reductase inhibitors)
Target / Mechanism
Inhibit HMG-CoA reductase, depleting mevalonate-pathway isoprenoids needed for RAS/RHO prenylation and some sterol-dependent growth programmes. Observational oncology signals are mixed and not a licence to treat cancer with statins.
Cancer relevance
Mevalonate-pathway blockade can affect prenylation of RAS-family GTPases. Observational human signals are mixed and confounding is substantial.
Mevalonate / prenylation mechanistic overlap. Convergence: RAS/RAF, Fatty-acid metabolism.
Target / Mechanism
Modest complex I inhibition raises AMP:ATP, activating and restraining hepatic and -linked anabolism. Direct antineoplastic efficacy is not established from that pharmacology alone.
Cancer relevance
activation and restraint provide a metabolic rationale in - and -linked tumours. Human data are mixed and do not establish metformin as cancer therapy.
Metabolic adjunctive research context. Convergence: AMPK, mTOR, Glycolysis.
Target / Mechanism
uncoupler in cestodes; mammalian models report , Wnt/β-catenin and modulation. Those host-signalling findings are investigational/preclinical.
Cancer relevance
Models report Wnt/β-catenin, and effects. Host signalling findings remain investigational.
Wnt / STAT3 signalling models. Convergence: Wnt/β-catenin, JAK/STAT, mTOR.
Research Context
- CRC TCGA. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330-337. https://doi.org/10.1038/nature11252
- CRC adenoma-carcinoma. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-767. https://doi.org/10.1016/0092-8674(90)90186-I
This oncology atlas is educational. Pathway maps, adjunctive strategies, and compound listings describe mechanistic relevance. They do not establish clinical efficacy, do not recommend treatment, and are not a substitute for oncology care. Evidence tiers are not equivalent.