Integrated Genomic and Pharmacological Approaches to Identify Synthetic Lethal Genes as Cancer Therapeutic Targets

Abstract The onset and development of malignant tumors are closely related to epigenetic modifications, and this has become a research hotspot. In recent years, a variety of epigenetic regulators have been discovered, and corresponding small molecule inhibitors have been developed, but their efficacy in solid tumors is generally poor. With the introduction of the first synthetic lethal drug (the PARP inhibitor olaparib in ovarian cancer with BRCA1 mutation), research into synthetic lethality has also become a hotspot. High-throughput screening with CRISPR-Cas9 and shRNA technology has revealed a large number of synthetic lethal pairs involving epigenetic-related synthetic lethal genes, such as those encoding SWI/SNF complex subunits, PRC2 complex subunits, SETD2, KMT2C, and MLL fusion proteins. In this review, we focus on epigenetic-related synthetic lethal mechanisms, including synthetic lethality between epigenetic mutations and epigenetic inhibitors, epigenetic mutations and non-epigenetic inhibitors, and oncogene mutations and epigenetic inhibitors.

Download Full-text

Cross-species synthetic lethal interaction screening as a strategy for the identification of novel therapeutic targets in cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.11105 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 11105-11105

Author(s):

John P. Shen ◽

Rohith Srivas ◽

Ana Bojorquez-Gomez ◽

Katherine Licon ◽

Jian Feng Li ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Synthetic Lethality ◽

Control Cell ◽

Therapeutic Targets ◽

Model Organisms ◽

Suppressor Genes ◽

Synthetic Lethal ◽

Synthetic Lethal Interactions ◽

Novel Therapeutic

11105 Background: Mutation, deletion, or epigenetic silencing of tumor suppressor genes is a near universal feature of malignant cells. However, therapeutic strategies for restoring the function of mutated or deleted genes have proven difficult. Synthetic lethality, an event in which the simultaneous perturbation of two genes results in cellular death, has been proposed as a method to selectively target cancer cells. Identifying and pharmacologically inhibiting proteins encoded by genes that are synthetic lethal with known tumor suppressor mutations should result in selective toxicity to tumor cells. Methods: To identify candidate target proteins we measured all pair-wise genetic interactions between all known orthologs of human tumor suppressor genes (162 genes) and all orthologs of druggable human proteins (~400 genes) in the model organism S. Cerevisiae. Analysis of the data uncovered 2,087 distinct synthetic lethal interactions between a tumor suppressor and druggable gene. A computational algorithm was then developed to identify those interactions which were likely to be conserved in humans based on conservation of the synthetic lethal relationship in the distant fission yeast S. pombe. Results: Our bioinformatic analysis suggested a high probability of conservation of the synthetic lethal interactions between the yeast RAD51 (ortholog of BRCA1) and RAD57 (ortholog of XRCC3) with HDA1 (a histone deacetylase; HDAC). We confirmed this by treating LN428 cells with stable lentiviral knockdown of BRCA1 or XRCC3 with the HDAC inhibitors vorinostat (SAHA) and entinostat (MS-275). Both the BRCA1 and XRCC3 knockdown cell lines were significantly more sensitive to HDAC inhibition relative to wild-type (non-silencing lentiviral control) cell line (Table). Conclusions: These results demonstrate that high-throughput approaches for screening synthetic lethal interactions in model organisms such as S. cerevisiae and S. pombecan serve as a valuable resource in helping to identify novel therapeutic targets in human cancer. [Table: see text]

Download Full-text

1067 Fascin and Cdk2 are synthetic lethal partners with exceptional potential as joint therapeutic targets in malignant melanoma

Journal of Investigative Dermatology ◽

10.1016/j.jid.2018.03.1080 ◽

2018 ◽

Vol 138 (5) ◽

pp. S181

Author(s):

S.P. Smith

Keyword(s):

Malignant Melanoma ◽

Therapeutic Targets ◽

Synthetic Lethal

Download Full-text

Abstract B34: High-throughput synthetic lethal interaction screening in model organisms as a strategy for the identification of novel therapeutic targets in cancer

10.1158/1557-3125.modorg-b34 ◽

2014 ◽

Author(s):

Rohith Srivas ◽

John Paul Shen ◽

Jian Feng Li ◽

Katherine Licon ◽

Ze Zhong Wang ◽

...

Keyword(s):

High Throughput ◽

Therapeutic Targets ◽

Model Organisms ◽

Synthetic Lethal Interaction ◽

Synthetic Lethal ◽

Interaction Screening ◽

Novel Therapeutic

Download Full-text

Synthetic Lethal Genetic Interactions That Decrease Somatic Cell Proliferation in Caenorhabditis elegans Identify the Alternative RFCCTF18 as a Candidate Cancer Drug Target

Molecular Biology of the Cell ◽

10.1091/mbc.e09-08-0699 ◽

2009 ◽

Vol 20 (24) ◽

pp. 5306-5313 ◽

Cited By ~ 23

Author(s):

Jessica McLellan ◽

Nigel O'Neil ◽

Sanja Tarailo ◽

Jan Stoepel ◽

Jennifer Bryan ◽

...

Keyword(s):

Cell Proliferation ◽

Caenorhabditis Elegans ◽

Somatic Cell ◽

Therapeutic Targets ◽

Genetic Interactions ◽

Assay System ◽

Cancer Drug ◽

Mild Phenotype ◽

Synthetic Lethal ◽

C Elegans

Somatic mutations causing chromosome instability (CIN) in tumors can be exploited for selective killing of cancer cells by knockdown of second-site genes causing synthetic lethality. We tested and statistically validated synthetic lethal (SL) interactions between mutations in six Saccharomyces cerevisiae CIN genes orthologous to genes mutated in colon tumors and five additional CIN genes. To identify which SL interactions are conserved in higher organisms and represent potential chemotherapeutic targets, we developed an assay system in Caenorhabditis elegans to test genetic interactions causing synthetic proliferation defects in somatic cells. We made use of postembryonic RNA interference and the vulval cell lineage of C. elegans as a readout for somatic cell proliferation defects. We identified SL interactions between members of the cohesin complex and CTF4, RAD27, and components of the alternative RFCCTF18 complex. The genetic interactions tested are highly conserved between S. cerevisiae and C. elegans and suggest that the alternative RFC components DCC1, CTF8, and CTF18 are ideal therapeutic targets because of their mild phenotype when knocked down singly in C. elegans . Furthermore, the C. elegans assay system will contribute to our knowledge of genetic interactions in a multicellular animal and is a powerful approach to identify new cancer therapeutic targets.

Download Full-text