Abstract IA13: Replication stress in cancer pathogenesis: Mechanisms and treatment opportunities

Replication stress (RS) induced by activated oncogenes and loss of some tumor suppressors is emerging as one of the hallmarks of cancer. The RS-induced DNA damage and the ensuing activation of cell cycle checkpoints commonly induce cellular senescence or cell death of the nascent tumor cells, providing an inducible intrinsic barrier to cancer progression. On the other hand, this scenario creates an environment that favors outgrowth of tumor cell clones featuring p53 mutations and other checkpoint defects such as those in ATM or Chk2 kinases, events that allow tumor growth at the expense of enhanced genomic instability. The ongoing enhanced RS, on the other hand, unmasks higher dependence of tumor cells on RS-support pathways such as those provided by the ATR-Chk1 axis and replication fork protective mechanisms, a vulnerability that can be targeted by inhibitors of ATR, Chk1, MK2 and Wee1 kinases, for example.The lecture will briefly outline this concept and then focus on our new data relevant for three of the open questions in this field:i) How are the molecular obstacles such as RNA-DNA hybrids and aberrant intermediates resulting from RS-causing collisions between replication and transcription resolved in cells?;ii) What is the impact of RS and the ensuing ATR signaling on the mutation spectra (mutation signatures) in major types of human solid tumors such as breast carcinomas?; andiii) How do human aggressive cancers such as glioblastomas cope with the excessive endogenous...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Replication Stress: Oral Presentations - Invited Abstracts Source Type: research