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Epigenetic based synthetic lethal strategies in human cancers.

ABSTRACT: Over the past decades, it is recognized that loss of DNA damage repair (DDR) pathways is an early and frequent event in tumorigenesis, occurring in 40-50% of many cancer types. The basis of synthetic lethality in cancer therapy is DDR deficient cancers dependent on backup DNA repair pathways. In cancer, the concept of synthetic lethality has been extended to pairs of genes, in which inactivation of one by deletion or mutation and pharmacological inhibition of the other leads to death of cancer cells whereas normal cells are spared the effect of the drug. The paradigm study is to induce cell death by inhibiting PARP in BRCA1/2 defective cells. Since the successful application of PARP inhibitor, a growing number of developed DDR inhibitors are ongoing in preclinical and clinical testing, including ATM, ATR, CHK1/2 and WEE1 inhibitors. Combination of PARP inhibitors and other DDR inhibitors, or combination of multiple components of the same pathway may have great potential synthetic lethality efficiency. As epigenetics joins Knudson's two hit theory, silencing of DDR genes by aberrant epigenetic changes provide new opportunities for synthetic lethal therapy in cancer. Understanding the causative epigenetic changes of loss-of-function has led to the development of novel therapeutic agents in cancer. DDR and related genes were found frequently methylated in human cancers, including BRCA1/2, MGMT, WRN, MLH1, CHFR, P16 and APC. Both genetic and epigenetic alterations may serve as synthetic lethal therapeutic markers.

SUBMITTER: Gao A

PROVIDER: S-EPMC7493427 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Epigenetic based synthetic lethal strategies in human cancers.

Gao Aiai A Guo Mingzhou M

Biomarker research 20200915

Over the past decades, it is recognized that loss of DNA damage repair (DDR) pathways is an early and frequent event in tumorigenesis, occurring in 40-50% of many cancer types. The basis of synthetic lethality in cancer therapy is DDR deficient cancers dependent on backup DNA repair pathways. In cancer, the concept of synthetic lethality has been extended to pairs of genes, in which inactivation of one by deletion or mutation and pharmacological inhibition of the other leads to death of cancer c ...[more]

PMID: 32974031

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Project description:The mutation status of cancer driver genes may correlate with different degrees of malignancy of cancers. The doubling time and multidrug resistance are 2 phenotypes that reflect the degree of malignancy of cancer cells. Because most of cancer driver genes are hard to target, identification of their synthetic lethal partners might be a viable approach to treatment of the cancers with the relevant mutations.The genome-wide screening for synthetic lethal partners is costly and labor intensive. Thus, a computational approach facilitating identification of candidate genes for a focus synthetic lethal RNAi screening will accelerate novel anticancer drug discovery.We used several publicly available cancer cell lines and tumor tissue genomic data in this study.We compared the doubling time and multidrug resistance between the NCI-60 cell lines with mutations in some cancer driver genes and those without the mutations. We identified some candidate synthetic lethal genes to the cancer driver genes APC, KRAS, BRAF, PIK3CA, and TP53 by comparison of their gene phenotype values in cancer cell lines with the relevant mutations and wild-type background. Further, we experimentally validated some of the synthetic lethal relationships we predicted.We reported that mutations in some cancer driver genes mutations in some cancer driver genes such as APC, KRAS, or PIK3CA might correlate with cancer proliferation or drug resistance. We identified 40, 21, 5, 43, and 18 potential synthetic lethal genes to APC, KRAS, BRAF, PIK3CA, and TP53, respectively. We found that some of the potential synthetic lethal genes show significantly higher expression in the cancers with mutations of their synthetic lethal partners and the wild-type counterparts. Further, our experiments confirmed several synthetic lethal relationships that are novel findings by our methods.We experimentally validated a part of the synthetic lethal relationships we predicted. We plan to perform further experiments to validate the other synthetic lethal relationships predicted by this study.Our computational methods achieve to identify candidate synthetic lethal partners to cancer driver genes for further experimental screening with multiple lines of evidences, and therefore contribute to development of anticancer drugs.

Dataset Information

Epigenetic based synthetic lethal strategies in human cancers.

Publications

Epigenetic based synthetic lethal strategies in human cancers.

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