Abstract P5-04-18: Identification of a novel combination therapy that prevents the metastatic outgrowth and reduces the viability of dormant breast cancer cells: implications for clinical translation

Abstract

Abstract Recurrent metastatic disease many years after initial therapy is a major cause of breast cancer (BC) mortality and strongly suggests that disseminated cells survive long periods in a growth-arrested state that is refractory to chemotherapy, known as “cellular dormancy.” Alterations in the components of the extracellular matrix (ECM), such as fibrotic foci and collagen-1 (Col-1) deposition, are associated with more aggressive breast cancer, increased metastasis and poor prognosis for BC patients. This suggests that ECM alterations may have a role in influencing the behavior of dormant BC cells. In fact, we have previously shown both in vitro (using 3-dimensional culture) and in vivo (preclinical model of fibrosis at the lung metastatic site) that alterations in the ECM surrounding disseminated, dormant BC cells can induce signaling pathways requiring Src and ERK1/2 activation that switch dormant cells into a proliferative state. We now demonstrate using the Src inhibitor AD0530 or Src shRNA, that the proliferative outbreak of dormant BC cells in Col-1-enriched microenvironments is prevented through the induction of a reversible G1-phase arrest and the upregulation of nuclear cyclin dependent kinase inhibitor p27Kip1, without affecting the viability of the dormant cells. Src inhibition, however, is not efficacious in regressing already established metastatic lesions, suggesting that Src signaling is crucial to engage the dormant-to-proliferative switch but is not necessary for survival once the cells have begun to proliferate. Since ERK1/2 activation is also required for the dormant-to-proliferative switch, we determined the effect of the MEK1/2 inhibitor AZD6244 that prevents ERK1/2 activation on the proliferative switch alone and in combination with the Src inhibitor. Importantly, we show that combination treatment with AZD0530 and the MEK1/2 inhibitor AZD6244 of dormant cells undergoing the dormant-to-proliferative switch induces apoptotic cell death in a significant fraction of the dormant cells, which is not seen with either inhibitor alone, and significantly delays metastatic outgrowth in the lung metastatic site. In conclusion, inhibition of Src alone prevents the proliferative response of dormant cells to external stimuli without affecting survival, but the addition of a MEK1/2 inhibitor suppresses survival of dormant cells, indicating that this combination may have clinical value in preventing breast cancer recurrence. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-04-18.