{"entity":{"id":"idea-ferroptosis-persisters","kind":"idea","name":"Kill drug-tolerant persisters through ferroptosis","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-08","links":[{"label":"Hangauer et al., Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition (Nature 2017)","url":"https://doi.org/10.1038/nature24297"}],"tags":["mechanism","open-question"],"related":[],"cancers":["nsclc","melanoma"],"sections":[],"technologies":["sbrt","liquid-biopsy"],"targets":["egfr","alk","braf"],"drugs":["osimertinib"],"companies":[],"institutions":["broad-institute","stanford"],"pathways":["ferroptosis-cell-death","emt","clonal-evolution"],"terms":["resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-hangauer-nature","paper-flaura-nejm-2018","paper-egfr-nsclc-lancet-oncol-2012","paper-egfr-nsclc-n-engl-j-med-2010"],"journals":[],"dependsOn":[],"notes":[],"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.","test":"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"},"route":"/ideas/idea-ferroptosis-persisters/","neighbours":{"cancer":[{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"drug":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"ferroptosis-cell-death","kind":"pathway","name":"Ferroptosis & regulated cell death","route":"/pathways/ferroptosis-cell-death/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"paper":[{"id":"paper-hangauer-nature","kind":"paper","name":"Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition","route":"/key-papers/paper-hangauer-nature/"},{"id":"paper-egfr-nsclc-lancet-oncol-2012","kind":"paper","name":"Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial","route":"/key-papers/paper-egfr-nsclc-lancet-oncol-2012/"},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/"},{"id":"paper-egfr-nsclc-n-engl-j-med-2010","kind":"paper","name":"Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR","route":"/key-papers/paper-egfr-nsclc-n-engl-j-med-2010/"}]}}