Tyrosine Kinase Signaling in Colorectal Cancer

Tyrosine kinases catalyse the transfer of phosphate groups to tyrosine residues on substrate proteins, initiating cascades that regulate cell proliferation, survival, migration and differentiation. In colorectal cancer, both receptor tyrosine kinases (RTKs) such as EGFR, c-MET and VEGFR, and non-receptor kinases exemplified by the SRC family, become dysregulated through mutation, overexpression or aberrant activation. Downstream effectors include the RAS–RAF–MEK–ERK pathway, the PI3K–AKT–mTOR axis and the JAK–STAT cascade, each contributing to malignant transformation, tumour growth and metastasis. Crosstalk with the WNT/β-catenin pathway further promotes cancer stem-cell maintenance and resistance to therapy. Clinically, inhibitors targeting EGFR or VEGFR have yielded improved outcomes in selected patient subsets, yet intrinsic and acquired resistance driven by feedback loops and secondary mutations remains a significant challenge. Ongoing research seeks to delineate the molecular context of tyrosine kinase signalling in colorectal cancer to refine patient stratification and develop combinatorial strategies that overcome adaptive resistance.

Research from Nature Portfolio

Investigations into molecular markers for advanced colorectal cancer have revealed that mutations in BRAF V600E and in SRC are independent predictors of prognosis and suitability for conversion surgery in stage IV disease. These alterations are largely mutually exclusive and correlate with distinct metastatic patterns, with SRC-mutant tumours favouring liver spread. Importantly, patients lacking both mutations exhibited higher rates of successful surgical conversion, underscoring the utility of these tyrosine kinase-associated biomarkers in guiding therapeutic decision-making and individualising surgical approaches.

Tyrosine Kinase Signaling in Colorectal Cancer publication trend

The graph below shows the total number of articles in tyrosine kinase signaling in colorectal cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Tyrosine kinase: An enzyme that transfers phosphate groups to tyrosine residues on proteins, modulating signal transduction.

Receptor tyrosine kinase (RTK): A membrane-spanning kinase activated by ligand binding, triggering intracellular signalling cascades.

Non-receptor tyrosine kinase: A cytosolic kinase activated by protein–protein interactions, not anchored to the plasma membrane.

SRC family kinases (SFKs): A group of non-receptor tyrosine kinases involved in cell adhesion, motility and proliferation.

STAT3: A transcription factor activated by tyrosine phosphorylation, promoting expression of genes linked to survival and inflammation.

BCL-2: An antiapoptotic protein that preserves mitochondrial integrity and inhibits programmed cell death.

c-MET: A receptor tyrosine kinase for hepatocyte growth factor, implicated in cell scattering, invasion and angiogenesis.

References

1. Targeting Receptor Kinases in Colorectal Cancer. Cancers (2019).
2. Regulation of Src Family Kinases during Colorectal Cancer Development and Its Clinical Implications. Cancers (2020).
3. Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether. Biomedicines (2023).
4. Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis. International Journal of Molecular Sciences (2020).
5. ICAM-1 promotes cancer progression by regulating SRC activity as an adapter protein in colorectal cancer. Cell Death & Disease (2022).
6. BRAF V600E and SRC mutations as molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer. Scientific Reports (2019).