OnCo
ideasIdea

Kill drug-tolerant persisters through ferroptosis

The cells that survive targeted therapy change shape and become unusually dependent on an antioxidant enzyme, GPX4. Hitting them in that window might stop resistance before it evolves.

Persister cells after EGFR, ALK, or BRAF inhibition are mesenchymal and GPX4-dependent (Viswanathan/Hangauer 2017); no drug-like GPX4 inhibitor exists, but xCT inhibitors, cyst(e)inase, and radiotherapy induce lipid peroxidation.

Hypothesis
A short ferroptosis-inducing pulse at the point of maximal response to a targeted agent eradicates persisters and prolongs progression-free survival compared with continuous targeted therapy alone.
Rationale
Persister GPX4 dependence is reproducible across models; the persister window is identifiable by ctDNA nadir; radiotherapy to residual lesions is a feasible ferroptosis inducer today.
What would test it
Randomised phase 2 in EGFR-mutant NSCLC: osimertinib alone vs osimertinib plus consolidative radiotherapy or an xCT inhibitor at ctDNA nadir; primary endpoint PFS; ferroptosis markers in on-treatment biopsies.
Maturity
preclinical evidence

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