Abstract The Triple Negative Breast Cancer (TNBC) sub-type is an aggressive form of breast cancer that is treated with chemotherapy, but recurrence rates are high. The majority of chemotherapy agents induce apoptotic tumor cell death via activation of executioner caspases. This activation of executioner caspases was previously thought to be the “point of no return” from cell death. However, a process termed “anastasis” has been identified that may allow a subset of tumor cells to adapt and survive chemotherapy induced apoptosis. We hypothesized that analysis of such cells will allow for the identification of adaptive molecular and metabolic rewiring mechanisms that can be targeted as vulnerabilities to prevent survival of tumor cells from chemotherapy via anastasis. Using a biosensor called CasExpress, which permanently labels cells surviving caspase activation with green fluorescence protein (GFP), our lab has identified and isolated sub-populations of TNBC cells surviving Paclitaxel induced apoptosis. The surviving “GFP+” cells exhibited increased resistance to Paclitaxel treatment and decreased expression of executioner caspase-3. Further analysis of these GFP+ cells has revealed ZEB1, a transcription factor, as a master regulator of molecular and metabolic rewiring promoting the accumulation of GFP+ cells during recovery from chemotherapy. ZEB1 is required for the survival of TNBC cells from chemotherapy induced apoptosis by sensitizing cells to ferroptosis, an iron-dependent mechanism of cell death caused by lipid peroxidation. ZEB1 carries this out by suppressing a lipid peroxide detoxifier protein, GPX4, and increasing the expression of ACSL4, a protein involved in the activation of Polyunsaturated Fatty Acids (PUFAs), which are highly susceptible to the lipid peroxidation causing ferroptosis. Remarkably, in the presence of ferroptosis inhibitors, Ferrostatin-1 or Trolox, the number of anastatic cells is significantly suppressed, demonstrating a requirement of ferroptosis sensitivity for TNBC cells to undergo anastasis and survive chemotherapy. This work ultimately identifies ZEB1 as a critical effector in anastasis, and identifies a potential vulnerability to treat patients with recurrent TNBC by targeting ferroptosis. Citation Format: Rachel Hausman, Wells Brown, Shannon Awrey, Denise J. Montell, Paul C. McDonald, Shoukat Dedhar. Survival of TNBC cells following taxol induced apoptotic caspase activation (anastasis) depends on enhanced ferroptosis sensitivity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4659.
Hausman et al. (Fri,) studied this question.