Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies.
Anna R MinchomCaterina AversaJuanita LopezPublished in: Therapeutic advances in medical oncology (2018)
Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit - for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.
Keyphrases
- dna damage response
- dna repair
- cell cycle
- immune response
- dna damage
- prostate cancer
- cell proliferation
- end stage renal disease
- small cell lung cancer
- induced apoptosis
- newly diagnosed
- chronic kidney disease
- ejection fraction
- cell free
- oxidative stress
- gene expression
- circulating tumor
- toll like receptor
- peritoneal dialysis
- endoplasmic reticulum stress
- copy number
- cell cycle arrest
- cancer therapy
- cell death
- drug delivery
- drug induced