This context dependence refers to synthetic lethal partner genes of oncogenes and tumor-suppressor genes under the original concept of SL

This context dependence refers to synthetic lethal partner genes of oncogenes and tumor-suppressor genes under the original concept of SL.11 However, in addition to the abnormities of synthetic lethal genes, the heterogeneity of tumor cells, its microenvironment, and external disturbances can affect genetic interactions, resulting in condition-dependent genetic interactions.110,111 Therefore, several synthetic lethal effects (at the gene, functional pathway, and organelle level) mentioned previously will be weaker or unachievable in the absence of particular conditions. 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. strong class=”kwd-title” Subject terms: Malignancy therapy, Cancer genetics, Oncogenes, Cancer metabolism Introduction Synthetic lethality (SL) initially originates from studies on fruit flies1,2 ELR510444 and yeast3C5 models. The original concept of SL is based on the simultaneous occurrence of abnormalities in the expression of two or more individual genes, including mutation, overexpression, or gene inhibition, which leads to cell death; whereas abnormality in only one of the genes does not affect cell viability (Fig. ?(Fig.1a1a).6C8 Tumor cells are the result of mutated or overexpressed genes in otherwise normal cells.9 Hence, inhibitors that target synthetic lethal partners of mutated or overexpressed genes in tumor cells can kill cancers without affecting the survival of normal cells. Open in a separate windows Fig. 1 Synthetic lethality classification. Synthetic lethality is divided into two major categories, nonconditional synthetic lethality and conditional synthetic lethality. a Nonconditional synthetic lethality. (i) Single mutation/overexpression of either gene A or B alone is viable in tumor cells. (ii) Inhibition of gene B or A in cells with a mutation/overexpression of gene A or B results in synthetic lethality. b Conditional synthetic lethality. (ii) Several synthetic lethal interactions may be dependent on certain intrinsic conditions, such as genetic background, hypoxia, high ROS, etc., or extrinsic conditions, such as DNA-damaging brokers and radiation. (i) Without these conditions, tumor cells with mutation/overexpression of both gene A and B could still survive. [c] Nonconditional synthetic lethality was further classified into gene level, pathway level, and organelle level according to the degree of studies into its mechanism in the review. Star shape of genes represents mutations; large rectangle represents genetic overexpression; syringe represents inhibitors; viable cells are depicted as ovals; and non-viable cells are depicted in random shapes With the advancement of tumor research, malignancy is now widely recognized as a disease of the genome. Various underlying tumor ELR510444 features, such as genome instability, give rise to the genetic diversity that accelerates their acquisition and inflammation.10 Therefore, targeting oncogenic driving genes, tumor-suppressor genes, and the underlying mechanisms is an applicable direction for cancer therapy.11 The development of genome sequencing and the analysis of thousands of human tumors led to the discovery of the first generation of genetically targeted cancer therapies.12C14 As a result, multiple personalized or precise genotype-targeted cancer treatments have been adopted and shown promising results in cancer patients that failed to respond to standard therapies.7,15,16 For instance, several studies have demonstrated that imatinib, a KIT inhibitor that is effective in treating patients with KIT-mutant gastrointestinal stromal tumors, had approximately 50% response rates and an extended median progression-free survival of 1 1.5 years.17C20 Imatinib also targets the BCR-ABL fusion tyrosine kinase for patients with chronic myelogenous leukemia.21C24 There are multiple studies that exhibit successful clinical outcomes,11 such as trastuzumab that target encoding HER2 in breast malignancy,25 erlotinib, or osimertinib for EGFR mutations in non-small-cell lung cancer (NSCLC), as well as crizotinib for ALK-positive lung cancer, as well as others.26C30 Although numerous small-molecule and antibody-based drugs for oncogenes or tumor-suppressor genes have proven to be effective ELR510444 for several tumors with certain gene mutations,31 not all oncogenes or tumor-suppressor genes could be targeted and resistance is common,7 In such cases, identifying and exploiting a second or several other functional genes that interact with the primary oncogene or tumor-suppressor gene provides an alternative method for cancer treatment. Therefore, SL is usually increasingly being explored recently, in an effort to identify new anticancer therapeutic targets through large-scale SL ELR510444 screening in model organisms and human cell lines such as NSCLC (NCI-H1355, NCI-H1299, NCI-H1155), EPHB2 hepatocellular carcinoma (HCC1954, HCC1937, HCC1806), and breast malignancy (MDA-MB-468, MDA-MB-436, MDA-MB-415) via clustered regularly interspaced short palindromic repeats (CRISPR),32 tumor genomic sequence database, RNA interference (RNAi) technology,33,34 etc. The most remarkable obtaining in SL is the hypersensitivity of BRCA1/2-mutant tumor cells to poly-(ADP-ribose) polymerase (PARP) inhibitors.35C37 Several PARP inhibitors (PARPi) were approved by the FDA for the treatment of breast malignancy and ovarian cancer in clinical practice.6,38 Furthermore, there have been various findings regarding classical oncogenic driving genes or tumor-suppressor genes, such as TP53, KRAS, MYC, etc.,39 which will be discussed in detail later. As our understanding of the complexity of cancer-cell signaling networks continues to grow, increasing.