A Comparative Genomic Approach for Identifying Synthetic Lethal Interactions in Human Cancer

Abstract

Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We describe a comparative genomic strategy for identifying cancer relevant synthetic lethal interactions whereby candidate interactions are prioritized based on genetic interaction data available in yeast, followed by targeted testing of candidate interactions in human cell lines. As proof of principle, we describe two novel synthetic lethal interactions in human cells discovered by this approach, one between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2. These results suggest therapeutic targets for cancers harboring mutations in SMARCB1 or ASPSCR1, and highlight the potential of a targeted, cross-species strategy for identifying synthetic lethal interactions relevant to human cancer.

Collateral Lethality: A New Therapeutic Strategy in Oncology

“…Attempts have been made to use biocomputational modeling approaches to infer relationships of biochemical/genetic redundancy between tumor suppressor genes and potential drug targets [67]. With the integration of the plentiful genetic and biochemical data from yeast [68], such approaches are becoming increasingly sophisticated.…”

A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy

“…Although the model organism approach is inherently limited to testing interactions of genes that are evolutionarily conserved, numerous such interactions have been observed, especially in the core conserved pathways in which TSGs are known to operate such as cell cycle, genome maintenance and metabolic growth (Roguev et al, 2008; Ryan et al, 2012). A number of TSGs important for human cancer were first identified and studied in yeast (Deshpande et al, 2013; Huang et al, 2003), which also provides an accessible model system in which to study mechanism of action (Simon et al, 2000). Nonetheless, it remains unclear to what extent synthetic lethal interactions observed in a model species can be ultimately translated for clinical application.…”

Building high-resolution synthetic lethal networks: a ‘Google map’ of the cancer cell

“…Similarly, SL interactions between RAD54B and SOD1 have been mapped from yeast to humans, with the inhibition of SOD1 leading to apoptosis in RAD54B-deficient colorectal cancer cells [30]. Also, systematic orthology mapping of yeast interactions has identified a SL relation between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2 [31]. By translating yeast interaction data, PP2A has been identified as a potential target due to its SDL relation with the spindle checkpoint protein MAD2, which is often overexpressed in cancer [27].…”