Abstract 51: Role of hematopoietic cell kinase (HCK) in breast cancer dormancy

Background: Triple negative breast cancer (TNBC) is an aggressive basal-like malignancy, which recurs more frequently than any other subtype of breast cancer. We recently discovered that TNBC can overcome drug pressure by switching to a hybrid basal-like (CD44 Hi ) and epithelial-like (CD24 Hi ) cell state, which is accompanied by a transient period of quiescence, or dormancy. These dormant, ‘hybrid9 cells highly express the phosphorylated SRC family kinase, hematopoietic cell kinase (HCK). Methods: Here, we used a panel of novel HCK inhibitors to study the effect of signaling-disruption in drug tolerance and tumor cell dormancy. Using flow cytometry and immunofluorescent microscopy we examined how HCK inhibition perturbs common features associated with dormancy such as proliferation and cell cycle status, intracellular levels of reactive oxygen species, and state of glucose metabolism. Finally, we validated the results using an ex-vivo human tumor model that predicts clinical response and recreates the native tumor microenvirnoment, CANscript TM . Results: We determined that targeted inhibition of HCK down-regulates the features of tumor cell dormancy and drug tolerance, eliminating cells with a hybrid mesenchymal-epithelial phenotype, diminishing polyploidy and hyper-G2 endoreduplication, and suppressing features of a dysregulated glycolytic state. Conclusion: Expression of HCK drives cancer cells to a quiescent cancer cells subpopulation, resulting in tolerance to chemotherapy. Targeted disruption of HCK overcomes these features of dormancy. HCK inhibitors could emerge as a novel treatment for chemotherapy-induced breast cancer dormancy. Citation Format: Sachin Khiste, Elliot Eton, Kevin Hodgetts, Hrvoje Lusic, Kodaganur Gopinath, S Krishnamurthy, Shiladitya Sengupta, Aaron Goldman. Role of hematopoietic cell kinase (HCK) in breast cancer dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 51.