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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.
This idea proposes killing drug-tolerant persisters through ferroptosis: cells surviving targeted therapy become dependent on the antioxidant enzyme GPX4, so hitting them in that window might stop resistance. Persisters after EGFR, ALK or BRAF inhibition are mesenchymal and GPX4-dependent (Viswanathan and Hangauer, 2017); no drug-like GPX4 inhibitor exists, but xCT inhibitors and radiotherapy induce lipid peroxidation. The hypothesis is that a short ferroptosis-inducing pulse at maximal response eradicates persisters and prolongs progression-free survival, timed by the ctDNA nadir on Liquid biopsy (ctDNA). The test is a randomised phase 2 in EGFR-mutant Non-small-cell lung cancer of Osimertinib alone against Osimertinib plus consolidative SBRT / SABR or an xCT inhibitor at ctDNA nadir.
Anyone diagnosed with advanced lung cancer should have EGFR testing before treatment, because osimertinib as the first drug gives the longest disease control, protects the brain, and is well tolerated. Chemotherapy is not the first step for these patients. The remaining questions are whether to intensify upfront (adding chemotherapy or amivantamab) and how to treat resistance when it develops.
One idea page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
One of the most cited trial reports Europe PMC returns for EGFR in Non-small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
One of the most cited trial reports Europe PMC returns for EGFR in Non-small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
Shares Stanford Health Care / Stanford Cancer Institute, Clonal evolution & minimal residual disease, EGFR, Liquid biopsy (ctDNA) and the tags mechanism, open-question.
Shares Clonal evolution & minimal residual disease, Non-small-cell lung cancer and the tags mechanism, open-question.
Shares Stanford Health Care / Stanford Cancer Institute and the tags mechanism, open-question.
Shares Stanford Health Care / Stanford Cancer Institute and the tags mechanism, open-question.
Shares Melanoma, Non-small-cell lung cancer and the tags mechanism, open-question.
Shares Melanoma, Non-small-cell lung cancer and the tags mechanism, open-question.
Shares Liquid biopsy (ctDNA) and the tags mechanism, open-question.
Shares Non-small-cell lung cancer and the tags mechanism, open-question.