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Table 1 Synthetic lethality definition and application

From: Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

Type Definition Application Reference
Synthetic lethality Synthetic sickness lethality The situation in which either of genes in a pair can be excluded without affecting cell viability, while the disruption in both genes concurrently results in cell death. It can be used to target cancers drove by tumor suppressor, which is genetically inactivated by mutation, resulting in the loss of the function of the protein. PARP shares a synthetic lethal relationship with BRAC1/2, both of which are key in DNA double-strand break repair. BRAC1/2 complete loss of function leaves cells extremely sensitive to PARP inhibitors, thereby presenting a therapeutic opportunity. [14, 17]
PI5P4K kinases are essential for cell growth in the absence of p53. Cancer cells with the overexpression of the PI5P4Kβ gene and p53 deficiency lead to senescence, due to the growth phenotype being accompanied by enhanced levels of reactive oxygen species. [18]
Synthetic dosage lethality Overexpression of one gene combined with the loss of function in another gene results in cell death, which can be used for targeting cancer cells with over-expressed, undruggable oncogenes. MAD2 shares synthetic dosage lethal interaction with PP2A. With the overexpression of MAD2, PP2A inhibition results in lethality in several tumors, including liver cancer, lung cancer, and malignant lymphoma. [19]
Histone deacetylases are necessary for tumors with the overexpression of TDP1 and the inhibition of PLK1 in CKS1B over-expressed cells causes cell death. [20]
Conditional synthetic lethality Conditional-dependent genetic interactions that depend on synthetic lethal interactions and the genetic background or environment and may account for the variation in synthetic lethal effects observed in different tumor cells. Cancer cells are usually accompanied with improperly folded proteins, leading proteotoxic stress and the need to increase proteasomal degradation and protein folding capacity for survival, via heat shock proteins upregulation, such as HSF1, HSP70, and HSP90. Interestingly, cancers bearing specific BRAF or EGFR mutations have an increased sensitivity to HSP90 inhibitors. [21]