Chemotherapy resistance: selection of pre-existing resistant clones
Chemotherapy kills sensitive cells, so it usually selects resistant clones (sub-populations of cells) already in a heterogeneous tumour (one with many clones that carry slightly different mutations), which expand.
Remember
Chemotherapy resistance usually arises because treatment selects resistant clones that were already in a heterogeneous tumour, and these clones then expand to regrow the tumour.
Memory aid
A selective weedkiller on a lawn
The weeds that survive were already tolerant, just as resistant clones were already present before chemotherapy, and they spread into the gaps left behind.
A tumour is not made of identical cells. It is heterogeneous: it holds many sub-populations (clones), each carrying slightly different mutations. Before any treatment, some clones may already be resistant to a given drug.
Chemotherapy kills the sensitive cells. Their death leaves space and nutrients, and the resistant clones use them to survive and multiply. This is clonal selection, followed by clonal expansion (one clone growing into a large population). So the tumour shrinks first and regrows later, now made mostly of cells that no longer respond to that drug.
An alternative to clonal expansion is chemotherapy-induced mutagenesis. Here the chemotherapy does not kill some cells outright, but damages their DNA just enough for them to mutate, which makes the tumour more heterogeneous. Chemotherapy can also add new mutations, but this is a separate mechanism.
The usual explanation is selection. The drug does not tell cells to mutate towards resistance. Chemotherapy kills sensitive clones and leaves the clones that were already resistant.
Key facts
- Starting point
- a tumour contains many clones with different mutations, and some clones may already be resistant to a drug before treatment begins.
- Selection
- chemotherapy kills sensitive clones and leaves resistant ones.
- Clonal expansion
- the surviving resistant clone regrows, so the tumour relapses.
- Pattern
- the tumour shrinks at first and later regrows, made mostly of cells that no longer respond to that drug.
- Usual explanation of the pattern
- selection of resistant clones that were already there.
- Separate mechanism
- chemotherapy-induced mutagenesis occurs when cells that are not killed outright have their DNA damaged just enough to mutate, which further increases the heterogeneity of the tumour.
Exam traps
- The drug does not instruct surviving cells to gain a mutation that blocks it, because mutations are not directed toward resistance and relapse is usually survival of clones that were already resistant.
- The immune system does not clear tumour clones according to whether they carry drug resistance; the sensitive cells die because of the chemotherapy.
- Genetic drift (a clone taking over by chance when numbers fall) has no regard to drug sensitivity, but the cells that end up dominating are drug-resistant, so survival was not random.
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