Replication stress and DNA damage response in tumorigenesis

Activation of oncogenes in cell culture models and tumorigenic events in early lesions of diverse types of human tumors evoke a DNA damage response (DDR) mediated by the ATR/ Chk1 and ATM/Chk2 kinase cascades activated by replication stress and the ensuing DNA double strand breaks (DSBs), respectively. DDR activation by oncogenes often leads to cellular senescence or cell death, however selection for defects that allow the nascent tumour cells to escape from the DDR-imposed barrier may facilitate tumour progression and affect responses to standard-of-care genotoxic therapies as well as the emerging DDR-targeted drugs such as PARP inhibitors. Our recently published and unpublished data provide further evidence that replication stress is involved in the observed activation of DDR signaling, and that this concept is applicable to a wide spectrum of malignancies. This presentation will illustrate the above issues by examples from functional and immunohistochemical analyses of gliomas, hematopoietic malignancies and breast cancer, documenting the dynamics and impact of DDR activation on cancer cells, including effects on biology of cancers stem cells, as well as impact of tumour associated DDR defects on acquired resistance of cancer cells to cisplatin and PARP inhibitors. Special emphasis will be on the mechanisms of replication stress in tumors, potential biomarkers of such stress, and the emerging concept of selective exploitation of replication stress in cancer treatment, using specific inhibitors of the ATR-Chk1 checkpoint signaling cascade.