Abstract P069: GDF15 contributes to the maintenance of the drug-tolerant persister state in cells responding to eribulin
Authors: Bellio Chiara , Emperador Marta , Zamora Esther , Serra Violeta , Saura Cristina , Littlefield Bruce A. , Villanueva Josep 
Published: December 2021

Abstract
A major obstacle in the fight against cancer is the development of drug resistance in response to therapy. Acquired resistance can be mediated by a small population of drug-tolerant persister cancer cells (DTPs), which are characterized by an increased capacity of adaptation to various stresses. DTPs are a small slow-cycling population of cells that tolerate cancer drugs, and most likely are responsible for generating a stable resistance. Growth differentiation factor 15 (GDF15) is a well-established marker of cellular stress. It is a member of the TGF-β superfamily, and while its physiological expression is barely detectable in most human somatic tissues, it is prominently induced under stress conditions to maintain cell and tissue homeostasis. Evidence suggests that GDF15 can be secreted in different cancer types. Nevertheless, GDF15 can have opposite effects depending on cellular context and disease stage, and further studies are needed to confirm its biological role in cancer. The working hypothesis of this study is that GDF15 plays a functional role in mediating the eribulin tolerance in DTP cells. MDA-MB-231 and MCF7 cell lines were treated for a month with an IC80 of eribulin. Initially, cells were sensitive to eribulin and approx. 85 % of the cells died after 7 days of treatment, then for about three weeks the surviving cells remained in a quiescent-DTP state. After approx. 3 weeks of treatment with a high dose of eribulin, cells started to proliferate in the presence of the drug, and we assume that at this point a stable mechanism of resistance is established. Interestingly, the analysis of the GDF15 levels during the chronic treatment showed that GDF15 expression/secretion was only detectable in the DTP state, suggesting a role of GDF15 in the maintenance of DTPs. To demonstrate the GDF15 protecting role against eribulin, we conducted loss of GDF15 function experiments, targeting both GDF15 and its receptor GFRAL. siGDF15 cells showed higher sensitivity to eribulin treatment than the siCTRL cells. We confirmed the same results targeting the GFRAL receptor, confirming an autocrine role of the secreted GDF15 in the cells that survive eribulin treatment. These results open the possibility for combining eribulin and a GDF15 antibody to specifically target DTP cells, and overcome eribulin resistance. Moreover, we envision that the circulating levels of GDF15 in metastatic breast cancer patients could be used as a pharmacodynamic biomarker during eribulin treatment. Furthermore, we are confident that GDF15 could help to better understand the onset of acquired resistance to eribulin in metastatic breast cancer patients.
Citation Format: Chiara Bellio, Marta Emperador, Esther Zamora, Violeta Serra, Cristina Saura, Bruce A. Littlefield, Josep Villanueva. GDF15 contributes to the maintenance of the drug-tolerant persister state in cells responding to eribulin [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P069.