KEY POINTS
- This narrative review primarily searched PubMed for literature addressing resistance to platinum compounds, temozolomide and 5-fluorouracil in chemoradiotherapy settings.
- The review was not conducted according to PRISMA and did not include a formal risk-of-bias assessment or quantitative evidence synthesis.
- The authors distinguish modality-specific initiating mechanisms from downstream survival programmes that may be shared by chemotherapy and radiotherapy resistance.
- Proposed shared mechanisms include reinforced DNA-damage responses, replication-stress management, redox buffering, mitochondrial metabolic remodelling, altered cell-fate decisions and stem-like tumour states.
- Platinum resistance is framed as a multilayered process involving drug transport, detoxification, DNA-adduct repair and resistant subpopulations. Temozolomide resistance is linked closely to MGMT and repair capacity.
- Mitochondrial plasticity and antioxidant systems may support cross-resistance by regulating reactive-oxygen-species tolerance and the energetic resources required for DNA repair.
- Potential therapeutic strategies include inhibition of DNA-damage-response pathways, PI3K-AKT-mTOR signalling, redox adaptation and stemness, but supporting evidence remains predominantly preclinical.
CLINICAL TAKEAWAY
Resistance during chemoradiotherapy should not automatically be attributed to one drug-specific pathway or intrinsic radiosensitivity. The framework may help structure translational studies, but it does not identify a validated biomarker or combination that should currently change clinical treatment.