Chemotherapy Resistance Mechanisms
Cancer cells develop resistance through drug efflux, target alterations, enhanced DNA repair, and antiapoptotic pathway activation.
## Overview
Drug resistance is the primary cause of treatment failure in oncology. Resistance can be intrinsic (present before therapy) or acquired (developed during treatment). Understanding resistance mechanisms guides the development of strategies to overcome or delay resistance.
## Multidrug Resistance (MDR): Efflux Pumps
P-glycoprotein (P-gp, MDR1, ABCB1) is an ATP-dependent efflux pump that actively exports chemotherapy drugs from cells, reducing intracellular concentrations. It transports taxanes, vinca alkaloids, anthracyclines, and many other drugs. MRP proteins (ABCC family) transport drug-glutathione conjugates. BCRP (ABCG2) exports methotrexate, irinotecan metabolites, and tyrosine kinase inhibitors. Overexpression of these transporters occurs in many resistant cancers.
## Target Alterations
Point mutations in drug targets reduce binding affinity: BCR-ABL T315I (imatinib), EGFR T790M (erlotinib/gefitinib), BRAF V600K/D/R (vemurafenib). Target amplification overwhelms drug concentrations: HER2 amplification overcomes anti-HER2 therapy. Alternative pathway activation bypasses the blocked target (MET amplification overcomes EGFR inhibition; upregulation of PI3K pathway in BRAF-inhibited melanoma).
## Enhanced DNA Repair
Nucleotide excision repair (NER) removes platinum adducts; high ERCC1 expression predicts cisplatin resistance in NSCLC and ovarian cancer. MGMT (O6-methylguanine-DNA methyltransferase) repairs temozolomide-induced damage; MGMT promoter unmethylated tumors are resistant. BRCA1/2 reversion mutations restore homologous recombination in PARP inhibitor-resistant ovarian cancer.
## Antiapoptotic Mechanisms
BCL-2/BCL-XL upregulation prevents cytochrome c release after DNA damage signals. Loss of caspase function (caspase-8 deletion in neuroblastoma) prevents activation of apoptosis cascade. TP53 mutation removes the guardian-of-genome that would trigger apoptosis after DNA damage — present in >50% of all cancers.
## Strategies to Overcome Resistance
Sequential targeted therapy (e.g., osimertinib after T790M emergence), combination regimens targeting non-overlapping pathways, and exploiting synthetic lethality (PARP inhibitors in BRCA-mutated cancers).
## Key Takeaways
- MDR efflux pumps (P-gp, MRP, BCRP) reduce intracellular drug concentrations
- Target mutations reduce drug binding (T315I, T790M); target amplification dilutes inhibition
- Enhanced NER reduces cisplatin efficacy; MGMT promoter methylation predicts temozolomide benefit
- TP53 loss and BCL-2 upregulation block apoptotic execution of DNA damage signals