Three usable sources of selectivity
- Reserve difference: the target tissue has less spare capacity, so the same inhibition pushes it past its limit first.
- Dependence difference: the target tissue relies on the pathway more heavily than normal cells, as a myeloma cell relies on the proteasome for immunoglobulin turnover.
- Context difference: the pathway is active only in the diseased tissue, so it can be targeted directly without affecting normal cells.
Resistance is an adaptation, not a failure of the drug
A cell that survives pathway inhibition restores the reserve the drug was meant to deplete, upregulates a parallel stress program, or raises target expression so the inhibitor is outcompeted. This is the same stress-adaptation logic applied to a drug. Blocking two reserves at once leaves less room to adapt, which is the rationale for combination therapy.
Four questions for evaluating a proposed therapy
- Which adaptive response is the disease depending on?
- What is the reserve difference between target and bystander tissue?
- What parallel program could the cell upregulate to compensate?
- What is the evidence that the target tissue cannot restore the depleted reserve?