DNA Double Strand Break Repair - Related Synthetic Lethality

Abstract

Cancer is a heterogeneous disease with a high degree of diversity between and within tumors. Our limited knowledge of their biology results in ineffective treatment. However, personalized approach may represent a milestone in the field of anticancer therapy. It can increase specificity of treatment against tumor initiating cancer stem cells (CSCs) and cancer progenitor cells (CPCs) with minimal effect on normal cells and tissues. Cancerous cells carry multiple genetic and epigenetic aberrations which may disrupt pathways essential for cell survival. Discovery of synthetic lethality has led a new hope of creating effective and personalized antitumor treatment. Synthetic lethality occurs when simultaneous inactivation of two genes or their products causes cell death whereas individual inactivation of either gene is not lethal. The effectiveness of numerous anti-tumor therapies depends on induction of DNA damage therefore tumor cells expressing abnormalities in genes whose products are crucial for DNA repair pathways are promising targets for synthetic lethality. Here, we discuss mechanistic aspects of synthetic lethality in the context of deficiencies in DNA double strand break repair pathways. In addition, we review clinical trials utilizing synthetic lethality interactions and discuss the mechanisms of resistance.

Keywords: DNA repair; PARP; anticancer therapy; double strand breaks (DSB); radiotherapy; synthetic lethality..