(323g) Matrix Stiffness Influences Response to Chemo and Targeted Therapy in Brain Metastatic Breast Cancer Cells

Breast cancer is the most common malignancy accounting for 12.5% of all newly diagnosed cancer cases across the globe. Breast cancer cells are known to metastasize to distant organs (i.e., brain), wherein they can exhibit a dormant phenotype for extended time periods. These dormant cancer cells exhibit reduced proliferation and resistance to therapy. However, the mechanisms by which the dormant cancer cells exhibit resistance to therapy, in the context of brain metastatic breast cancer (BMBC), is not well understood. In this study, we employed hyaluronic acid (HA) hydrogels with varying stiffnesses (i.e., ~0.4 kPa vs. ~4.5 kPa) to study drug responsiveness in dormant vs. proliferative BMBC cells. We found that cells cultured on soft HA hydrogels (~0.4 kPa) that showed a non-proliferative (dormant) phenotype exhibited resistance to Paclitaxel or Lapatinib as tested using proliferation and apoptosis assays. In contrast, cells cultured on stiff HA hydrogels (~4.5 kPa) that showed a proliferative phenotype exhibited responsiveness to Paclitaxel or Lapatinib. Moreover, dormancy-associated resistance was found to be due to upregulation of serum/glucocorticoid regulated kinase 1 (SGK1) gene which was mediated, in part, by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Finally, we inhibited the expression of SGK1 using a SGK inhibitor (GSK650394) in BMBC cells cultured on soft HA hydrogels, which resulted in a dormant-to-proliferative switch and response to therapy. Overall, our study demonstrated that matrix stiffness influences dormancy-associated therapy response and that the p38/SGK1 axis, in part, mediates therapy response in our HA hydrogel platform.