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2016 ; 7
(8
): ä Nephropedia Template TP
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Targeting DNA Replication Stress for Cancer Therapy
#MMPMID27548226
Zhang J
; Dai Q
; Park D
; Deng X
Genes (Basel)
2016[Aug]; 7
(8
): ä PMID27548226
show ga
The human cellular genome is under constant stress from extrinsic and intrinsic
factors, which can lead to DNA damage and defective replication. In normal cells,
DNA damage response (DDR) mediated by various checkpoints will either activate
the DNA repair system or induce cellular apoptosis/senescence, therefore
maintaining overall genomic integrity. Cancer cells, however, due to constitutive
growth signaling and defective DDR, may exhibit "replication stress" -a
phenomenon unique to cancer cells that is described as the perturbation of
error-free DNA replication and slow-down of DNA synthesis. Although replication
stress has been proven to induce genomic instability and tumorigenesis, recent
studies have counterintuitively shown that enhancing replicative stress through
further loosening of the remaining checkpoints in cancer cells to induce their
catastrophic failure of proliferation may provide an alternative therapeutic
approach. In this review, we discuss the rationale to enhance replicative stress
in cancer cells, past approaches using traditional radiation and chemotherapy,
and emerging approaches targeting the signaling cascades induced by DNA damage.
We also summarize current clinical trials exploring these strategies and propose
future research directions including the use of combination therapies, and the
identification of potential new targets and biomarkers to track and predict
treatment responses to targeting DNA replication stress.
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