Authors
Mathéa Geraud, Remi Gence, Anne Casanova, Estelle Taranchon-Clermont, Simona Salimbeni, Nesibe Özsu, Maina Vienne, Célia Delahaye, Elodie Borrull, Amélie Lusque, Mathilde Morisseau, Thomas Filleron, Delphine Pagan, Camille Taha, Agnese Cristini, Julien Mazières, Olivier Calvayrac, Gilles Favre, Anne Pradines, Olivier Sordet
Published in
Science advances. Volume 12. Issue 39. Pages eaeh9099. Sep 25, 2026. Epub Sep 23, 2026.
Abstract
Resistance to targeted cancer therapies often arises from drug-tolerant cells, which survive treatment by entering a nonproliferative state. Over time, these cells can acquire mutations that contribute to cell reproliferation, but how nonproliferating drug-tolerant cells accumulate these mutations remains unclear. Here, we show that EGFR inhibition in EGFR-mutated lung cancer transiently down-regulates tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme that resolves abortive topoisomerase I cleavage complexes (TOP1ccs). In drug-tolerant cells, elevated reactive oxygen species promote TOP1cc trapping, while TDP1 down-regulation impairs their repair, driving TOP1cc accumulation, resistance mutation acquisition, and cell reproliferation. We further find that TDP1 expression is absent in ∼25% of EGFR-mutated lung cancers. In TDP1-deficient cells, combining EGFR inhibition with a sublethal concentration of topotecan, which further increases TOP1ccs, abolishes cell reproliferation. Together, these findings establish persistent TOP1cc accumulation as a driver of therapy-induced mutagenesis linking drug tolerance to adaptive resistance and reveal TDP1 loss as a targetable vulnerability in EGFR-mutated lung cancers.
PMID:
42777032
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 18
- Comments 0