Journal
CELL REPORTS
Volume 23, Issue 7, Pages 2095-2106Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.04.068
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Funding
- Department of Defense Era of Hope Scholar Award [W81XWH-10-1-0558]
- NCI [T32CA186892]
- Susan G. Komen [PDF17483544]
- Cancer Prevention Research Institute of Texas [RP110532]
- NIH/National Cancer Institute [P30CA016672]
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Extensive spontaneous DNA damage from noncogene-induced replication stress is ubiquitous in precancerous lesions. While this damage induces differentiation, senescence, or apoptosis in normal cells, defects in DNA replication stress response (RSR) allow cells to continue proliferating, ultimately leading to early tumorigenesis. Using systems-level approaches, we developed a replication stress response defect gene signature that predicted risk of cancer development from hyperplastic lesions. Intriguingly, we found that replication stress response defects rewire non-malignant cells into a cancer stem cell (CSC)-like state, and analysis of CSCs indicated that they inherently harbor replication stress response defects. High-throughput drug screening to elucidate molecules required for survival of replication stress response defective cells identified a dependence on MEK/ERK signaling. Inhibition of this signaling cascade restored oncogene-induced senescence through a p53-independent MDM2/p21 axis. Moreover, MEK/ERK inhibition also depleted CSC populations. Together, these findings provide insights into the role of replication stress response defects in CSCs and an actionable pathway for therapeutic targeting.
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