Abstract 35: Evolution of resistance to glucocorticoid receptor agonists

Chemotherapy resistance is a major obstacle to curing cancer patients. Over 90% of metastatic tumors are resistant to chemotherapy, leading to treatment failure. Although glucocorticoid receptor agonists (GRAs) are a very commonly used class of component drugs in front-line combination chemotherapies for hematopoietic cancer, our understanding of its mechanism(s) of action and resistance are very limited. Here using a preclinical murine model of Burkitt's lymphoma, we investigated the mechanism of resistance to the glucocorticoid receptor agonist dexamethasone. Dose responses of dexamethasone on the parental Eμ-myc; Arf-null cell line revealed a consistently small population of persistent survivors, suggesting a pre-existing subpopulation with innate dexamethasone resistance. To further address the evolution and selection of these survivors in the presence of GRAs, we derived resistant cell lines in vitro by treating the parental cell line with dose escalating concentrations of dexamethasone. These resistant cell lines were expectedly cross-resistant to other GRAs. However, loss of expression of the glucocorticoid receptor (GR) was not observed – ruling out one possible resistance mechanism. To explore alternative or downstream pathways that may be implicated, we subsequently acquired dose responses against a broad set of targeted kinase inhibitors, and observed modest sensitivity to the HSP90 inhibitor 17-AAG. This suggests that the resistance mechanism could be related to HSP90's role of holding ligand-free glucocorticoid receptor (GR) in the cytoplasm. We are now re-evolving the parental populations, and deriving clonal populations to confirm this phenotype. A better understanding of how hematopoietic cancer cells evolve resistance to GCAs will lead to improved design of drug combinations for prolonged survival.

Citation Format: Simona Dalin, Boyang Zhao, Michael T. Hemann. Evolution of resistance to glucocorticoid receptor agonists. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 35.