title: Selumetinib produces a central core of apoptosis in breast cancer bone metastases in mice.
abstract: Bone is a common site for metastatic colonization in patients with breast cancer, hence the importance of identifying new treatments for this disease. Preclinical studies of bone metastases have commonly employed MDA-MB-231 cells that possess an activated KRAS allele. While activating RAS mutations are relatively rare in human breast cancer, increased RAS-RAF-MEK pathway activity is common in high-grade breast cancers. To study the consequences of MEK inhibition on bone metastases stemming from the intra-cardiac injection of luciferase-expressing MDA-MB-231 cells in mice, we used the MEK inhibitor AZD6244 (Selumetinib). We found that AZD6244 treatment caused decreased tumor bioluminescence that was associated with cavitation of the bone metastases, owing to apoptosis of cells specifically within the central region of the bone lesions. Hypothesizing that the latter effect was due to the increased sensitivity of poorly perfused regions to pro-apoptotic stimuli, we found that the combination of serum deprivation and AZD6244 led to dramatic induction pf MDA-MB-231 apoptosis in vitro. Our results suggest that MEK inhibition may be a strategy for triggering cell death within the hypoperfused, oxygen and nutrient poor regions of tumors with activated RAS alleles.
authors.affiliation: Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health University of Calgary, Calgary, Alberta, Canada.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Bosma
authors.affiliation: Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health University of Calgary, Calgary, Alberta, Canada.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Singla
authors.affiliation: Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health University of Calgary, Calgary, Alberta, Canada.
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Downey
authors.affiliation: Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health University of Calgary, Calgary, Alberta, Canada.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
keywords: AZD6244 (Selumetinib); activated KRAS; apoptosis; bioluminescence imaging; bone metastases; triple-negative breast cancer