Development of synthetic lethality in cancer: molecular and cellular classification

Abstract

Recently, genetically targeted cancer therapies have been a topic of great interest. Synthetic lethality provides a new approach for the treatment of mutated genes that were previously considered unable to be targeted in traditional genotype-targeted treatments. The increasing researches and applications in the clinical setting made synthetic lethality a promising anticancer treatment option. However, the current understandings on different conditions of synthetic lethality have not been systematically assessed and the application of synthetic lethality in clinical practice still faces many challenges. Here, we propose a novel and systematic classification of synthetic lethality divided into gene level, pathway level, organelle level, and conditional synthetic lethality, according to the degree of specificity into its biological mechanism. Multiple preclinical findings of synthetic lethality in recent years will be reviewed and classified under these different categories. Moreover, synthetic lethality targeted drugs in clinical practice will be briefly discussed. Finally, we will explore the essential implications of this classification as well as its prospects in eliminating existing challenges and the future directions of synthetic lethality.

On the Road to Fight Cancer: The Potential of G-Quadruplex Ligands as Novel Therapeutic Agents

“…The concept of synthetic lethality refers to a genetic setting where the simultaneous occurrence of abnormalities (e.g., mutation, overexpression, or inhibition of gene function) in the expression of two or more separate genes leads to cell death; whereas abnormality in only one of the genes does not affect cell viability [ 80 ]. Since tumor cells are the result of altered gene expression, inhibitors that target the synthetic lethal partners of these mutated or overexpressed genes can lead to cancer cell death without affecting the survival of normal cells [ 80 ]. As a consequence, the synthetic lethality has a tremendous therapeutic potential in cancer [ 81 ].…”

“…Indeed, the product of a gene that has a synthetic lethal interaction with a cancer-specific somatic or germline mutation would represent a suitable candidate for drug targeting and a therapeutic agent that exploits such a synthetic lethal interaction would result in a favorable therapeutic index [ 81 ]. This notion has been elegantly exemplified by the success of PARP inhibitors in BRCA -mutant cancers, that has represented the first example of a synthetic lethality-based therapeutic approach, resulting in the approval of the PARP-1 inhibitor olaparib for the treatment of advanced-stage, BRCA1/2 -mutant ovarian cancers in 2014 [ 80 ].…”

“…In addition, it has been reported that the G4 ligand CX-5461 exerts a marked cytoxic effect in BRCA-deficient cancer cells and in patient-derived xenograft models, including tumors resistant to PARP inhibition [85]. Although the identification of clinically relevant synthetic lethal interactions is still a major hurdle in Oncology [80,81], a genome-wide study has been recently carried out to systematically identify human genes the silencing of which promote cancer cell death in the presence of G4 ligands [86]. Genetic vulnerabilities, both in terms of genes and pathways, were indeed revealed and four genes (BRCA1, TOP1, DDX42 and GAR1) were validated by an independent RNAi-mediated approach as key "G4 sensitizer" genes in melanoma and fibrosarcoma cell lines exposed to PDS or Phen DC3 [86].…”

Hypoxia Signaling in Cancer: From Basics to Clinical Practice

“…The importance of the latter is that hypoxia-induced metabolic processes (e.g. in case of anti-angiogenic treatments) have to be taken into account since using inhibitors of metabolic adaptation regulators (such as mTOR) or other enzymes, metabolic catastrophe, synthetic lethality could be induced in cancer cells [ 47 , 48 ].…”

Artificial intelligence in gastroenterology and hepatology: Status and challenges

“…Furthermore, AI could be used to process the data generated from the tissue-on-a-chip platform which could better summarize the tumor microenvironment, thus reach precise and individual chemotherapy in gastroenterology and hepatology. As synthetic lethality becomes a promising genetically targeted cancer therapy[ 152 , 153 ], AI could also be used for the detection of target synthetic lethal partners of overexpressed or mutated genes in tumor cells to kill cancers. Finally, AI tools could not replace endoscopists, radiologists, and pathologists in the near and even distant future.…”