Synthetic Lethality-based Identification of Targets for Anticancer Drugs in the Human Signaling Network

Abstract

Chemotherapy agents can cause serious adverse effects by attacking both cancer tissues and normal tissues. Therefore, we proposed a synthetic lethality (SL) concept-based computational method to identify specific anticancer drug targets. First, a 3-step screening strategy (network-based, frequency-based and function-based screening) was proposed to identify the SL gene pairs by mining 697 cancer genes and the human signaling network, which had 6306 proteins and 62937 protein-protein interactions. The network-based screening was composed of a stability score constructed using a network information centrality measure (the average shortest path length) and the distance-based screening between the cancer gene and the non-cancer gene. Then, the non-cancer genes were extracted and annotated using drug-target interaction and drug description information to obtain potential anticancer drug targets. Finally, the human SL data in SynLethDB, the existing drug sensitivity data and text-mining were utilized for target validation. We successfully identified 2555 SL gene pairs and 57 potential anticancer drug targets. Among them, CDK1, CDK2, PLK1 and WEE1 were verified by all three aspects and could be preferentially used in specific targeted therapy in the future.

p21 in Cancer Research

“…PAK4 overexpression was shown to cause drug resistance and poor survival in gastric cancer patients; knocking down PAK4 induced apoptosis in PAK4 overexpressing gastric cell lines [110]. In a network-based screening method, PAK1 was mapped into many synthetic lethality pathways, such as MAPK signaling, ErbB (Erythroblastic leukemia viral oncogene homologue) signaling, and focal adhesion pathways [111]. PAK1 inhibition in a mouse model of Kras-driven squamous cell carcinoma was shown to suppress tumorigenesis, following loss of Erk and Akt activity.…”

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

“…Minor progress has been made via high-throughput drug screens in several tumors including cyclin-dependent kinase 1/2 (CDK1/2)-, polo-like kinase 1 (PLK1)-, and WEE1-mutated cancers. Drug screens are mainly based on both mutation data and high-throughput drug screening data to identify sensitive mutations that may constitute synthetic lethal interactions [ 74 ]. Notably, identifying the synthetic lethal interactions through drug screens are reciprocal.…”

Development of synthetic lethality in cancer: molecular and cellular classification

“…It could explain the controversies in previous studies, such as the synthetic lethal effect between STK33 and KRAS mentioned above, and provide the basis for further study on more complex conditions using the theory of conditional SL. 61 , 62 Synthetic lethal screening technologies including drug screens, 133 RNAi screens, 33 bioinformatics screens, 34 CRISPR screens, 32 and combination of these methods, 11 provide the possibility for geneticists to achieve this. At the gene level, many previous studies have focused on identifying a synthetic lethal relationship between two genes.…”