GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells

SIMPLE SUMMARY: Drug tolerant persister (DTP) cells are a unique, small sub-population of cancer cells that maintain viability under anti-cancer cytotoxic treatments. These cells enter into a reversible drug-tolerant state, which is believed to be the root of tumor recurrence. Therefore, there is a great need to find novel ways to monitor and eliminate DTP cells. We have identified the secretion of GDF15 as a response biomarker of eribulin treatment, as well as a specific biomarker of DTP cells in breast cancer. GDF15 expression is low or absent in cells sensitive to eribulin, strongly upregulated during response to the drug, and then downregulated when stable resistance is ultimately established. We have also shown that GDF15 plays a direct role in the survival of DTP cells. Thus, targeting GDF15 could help eradicate DTP cells and block the onset of stable acquired resistance. Most importantly, our data suggest that the combination of eribulin plus a GDF15 neutralizing antibody might be beneficial in the treatment of breast cancer. ABSTRACT: Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after drug treatment. We performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. We showed that the growth differentiation factor 15 (GDF15) is a protein significantly over-secreted upon eribulin treatment. The biomarker potential of GDF15 was confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. We also found that GDF15 is required for survival of DTP cells. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function assays. Finally, we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired resistance.