Chemotherapy Resistance Mechanisms in Colorectal Cancer

Colorectal cancer (CRC) frequently develops resistance to standard chemotherapeutics such as 5-fluorouracil (5-FU), oxaliplatin and irinotecan, undermining patient outcomes. Resistance arises through several intertwined processes. Intrinsic or acquired upregulation of drug-metabolising enzymes such as thymidylate synthase, dihydropyrimidine dehydrogenase and dUTPase alters drug availability and efficacy. Enhanced DNA repair pathways and checkpoint kinase activity mitigate cytotoxic lesions and sustain cell survival. Evasion of apoptosis may reflect alterations in p53 signalling or downstream effectors. A subpopulation of cancer stem cells (CSCs), often enriched after treatment, fuels recurrence via activation of the WNT/β-catenin axis and other stemness programmes. Crosstalk with the tumour microenvironment—including tumour-associated macrophages (TAMs), fibroblasts and endothelial cells—supports survival, angiogenesis and epithelial-mesenchymal transition (EMT). Epigenetic reprogramming, non-coding RNA dysregulation, autophagy modulation and redox homeostasis further contribute to multifactorial resistance. Understanding these mechanisms has informed novel combinatorial strategies and targeted therapeutics to overcome refractory disease.

Research from Nature Portfolio

Recent studies have shown that 5-FU treatment can paradoxically enrich CSCs through p53-mediated upregulation of WNT3 and subsequent activation of the WNT/β-catenin pathway in mouse models and patient-derived organoids. Concurrent inhibition of WNT signalling alongside 5-FU prevents CSC expansion, reduces tumour regrowth and improves long-term response. Another line of enquiry has revealed that MEK inhibitors, while suppressing RAS-MAPK signalling, inadvertently activate WNT/β-catenin, driving stem cell plasticity and potential relapse. This unexpected feedback underscores the need to tailor targeted kinase inhibitors alongside modulators of stemness pathways to forestall acquired resistance.

Chemotherapy Resistance Mechanisms in Colorectal Cancer publication trend

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

Technical terms

Cancer stem cells (CSCs): A subpopulation of tumour cells with self-renewal capacity responsible for recurrence and metastasis.

Epithelial-mesenchymal transition (EMT): A process by which carcinoma cells acquire migratory and invasive traits.

Thymidylate synthase: An enzyme involved in DNA synthesis and a primary target of 5-FU.

dUTPase: An enzyme that hydrolyses dUTP, its overexpression can confer resistance by preventing misincorporation of uracil analogues.

WNT/β-catenin pathway: A signalling cascade crucial for stem cell maintenance and often dysregulated in CRC.

Tumour-associated macrophages (TAMs): Immune cells within the tumour microenvironment that can promote chemoresistance and tumour progression.

References

1. Synthesis and characterisation of a nucleotide based pro-drug formulated with a peptide into a nano-chemotherapy for colorectal cancer. Journal of Controlled Release (2024).
2. 7S,15R-Dihydroxy-16S,17S-epoxy-docosapentaenoic Acid Overcomes Chemoresistance of 5-Fluorouracil by Suppressing the Infiltration of Tumor-Associated Macrophages and Inhibiting the Activation of Cancer Stem Cells in a Colorectal Cancer Xenograft Model. Marine Drugs (2023).
3. 5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation. Nature Communications (2020).
4. MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer. Nature Communications (2019).
5. Identification of Genes Related to 5-Fluorouracil Based Chemotherapy for Colorectal Cancer. Frontiers in Immunology (2022).