ideasIdea
Turn off the error-prone repair that manufactures resistance mutations
Under treatment stress, cancer cells switch on sloppy DNA copying that generates the mutations they need to survive. Blocking that machinery could stop resistance being invented.
Stress-induced mutagenesis through translesion synthesis polymerases (REV1, POLZ) accelerates the emergence of resistance in bacteria and in cancer cells. REV1 inhibitors have been described and shown to reduce chemotherapy-induced mutagenesis and delay resistance in models. Given as an adjunct rather than a cytotoxic, the aim is to lower the mutation supply rate rather than to kill cells.
Hypothesis
Co-administration of a translesion synthesis inhibitor with chemotherapy or targeted therapy reduces the acquisition of new resistance mutations and prolongs time to progression in vivo.
Rationale
Resistance requires variation; reducing the rate at which variation is generated is a validated strategy against bacterial resistance and has direct molecular counterparts in cancer.
What would test it
In vivo resistance-emergence studies with and without a REV1 inhibitor, using barcoded models to distinguish selection of pre-existing clones from newly generated mutations.
Maturity
preclinical evidence
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
7
Bottlenecks it attacks
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.