Abstract

Cancer is a major cause of death throughout the world, and there is a large need for better and more personalized approaches to combat the disease. Over the past decade, synthetic lethal approaches have been developed that are designed to exploit the aberrant molecular origins (i.e. defective genes) that underlie tumorigenesis. BLM and CHEK2 are two evolutionarily conserved genes that are somatically altered in a number of tumor types. Both proteins normally function in preserving genome stability through facilitating the accurate repair of DNA double strand breaks. Thus, uncovering synthetic lethal interactors of BLM and CHEK2 will identify novel candidate drug targets and lead chemical compounds. Here we identify an evolutionarily conserved synthetic lethal interaction between SOD1 and both BLM and CHEK2 in two distinct cell models. Using quantitative imaging microscopy, real-time cellular analyses, colony formation and tumor spheroid models we show that SOD1 silencing and inhibition (ATTM and LCS-1 treatments), or the induction of reactive oxygen species (2ME2 treatment) induces selective killing within BLM- and CHEK2-deficient cells relative to controls. We further show that increases in reactive oxygen species follow SOD1 silencing and inhibition that are associated with the persistence of DNA double strand breaks, and increases in apoptosis. Collectively, these data identify SOD1 as a novel candidate drug target in BLM and CHEK2 cancer contexts, and further suggest that 2ME2, ATTM and LCS-1 are lead therapeutic compounds warranting further pre-clinical study.

Highlights

  • Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide

  • To identify novel and lead candidate drug targets to evaluate in a CRC context, we recently employed a cross-species candidate gene approach and identified the synthetic lethal (SL) interactors of yeast genes whose human orthologs are somatically altered in CRC

  • Excessive reactive oxygen species (ROS) induce a variety of cellular damage including double strand break (DSB), which we presumed would not be accurately repaired in homology directed repair (HDR)-defective cells (e.g. BLM and CHEK2-deficient), and would underlie cell cytotoxicity

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Summary

Introduction

In 2015, the American Cancer Society estimates that ~132,700 Americans will be newly diagnosed and ~50,000 additional individuals will succumb to the disease in 2015 [1]. These statistics highlight the need for novel personalized therapeutic strategies designed to better combat the disease. A cancer-driving mutation is leveraged to lethality through the down-regulation (i.e. silencing or inhibition) of a synthetic lethal (SL) interactor (i.e. drug target) [2]. Identifying SL interactors of genes somatically altered in cancer will uncover novel candidate drug targets whose inhibitors represent lead therapeutic agents

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