Abstract 993: GDF15 is a candidate circulating biomarker of eribulin response in breast cancer
Authors: Bellio Chiara , Emperador Marta , Garrigós Laia , Zamora Esther , Saura Cristina , Littlefield Bruce A. , Villanueva Josep 
Published: July 2021

Microtubule-targeting agents (MTAs) constitute a diverse group of chemical compounds that bind to microtubules and affect their structure and function. Disruption of microtubules induces various cellular responses, often leading to cell cycle arrest or cell death. Eribulin is a microtubule dynamic inhibitor approved for treatment in patients with metastatic breast cancer (MBC) who had previously been administered chemotherapy. Although MTAs are widely used in the clinic, there is a research gap in the identification of pharmacodynamic (PD) biomarkers that could be used as surrogates during the course of treatment and measured non-invasively. The proteomic interrogation of the cancer secretome has emerged as a promising strategy for biomarker and drug target discovery. Secretomes have much lower complexity than plasma and tissue homogenates and are likely to be enriched with tumour derived-proteins entering into circulation. Quantitative proteomics analysis of the cancer secretome could help monitor critical aspects of cancer progression and therapeutics. The working hypothesis for this study is that eribulin induces a specific secretome that can be measured by quantitative proteomics, and could be used to identify response biomarkers linked to the action of the drug. We used three cell line models, MDA-MB-231 and HS578T (representing triple-negative BC) and MCF7 (representing luminal BC), all of them sensitive to treatment with eribulin. After a 7-day treatment with an IC70 of eribulin, we identified a subpopulation of cells with a lower proliferation rate, a slow-cycling subpopulation of cells that survived the large cell death induced by the drug. This slow-cycling population is alive in the presence of eribulin but remains in a quiescent state. The secretome profiling of slow-cycling cells revealed an oversecretion of the growth differentiation factor 15 (GDF15) when compared to parental cells and cells that after continuous exposure to eribulin start proliferating and become drug-tolerant. Interestingly, drug-tolerant cells lose the secretion of GDF15, suggesting a role for GDF15 in the response to eribulin treatment. Currently, we are validating GDF15 as a candidate circulating biomarker for the response to eribulin in patient-derived xenograft (PDX) 3D-models derived from metastatic BC patients. Furthermore, we are conducting loss of GDF15 function experiments in slow-cycling cells to understand whether the secretion of GDF15 could also contribute to the establishment and/or maintenance of the slow-cycling state in cells responding to eribulin.We envision that our work will contribute to the validation of GDF15 as a circulating biomarker that could be used to monitor eribulin's activity in the clinical setting. Furthermore, these results could also help understand the initiation of acquired resistance to eribulin.

Citation Format: Chiara Bellio, Marta Emperador, Laia Garrigós, Esther Zamora, Cristina Saura, Bruce A. Littlefield, Josep Villanueva. GDF15 is a candidate circulating biomarker of eribulin response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 993.