A Road Map to Personalizing Targeted Cancer Therapies Using Synthetic Lethality

Parameswaran, Sreejit; Kundapur, Deeksha; Vizeacoumar, Frederick S.; Freywald, Andrew; Uppalapati, Maruti

doi:10.1016/j.trecan.2018.11.001

Cited by 24 publications

(17 citation statements)

References 138 publications

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“…In these instances, the SLIs we have identified will not work. While there are several genes that are either up- or down-regulated in multiple cancers, in the context of synthetic lethality, only those patients with low expression of FBXW7 will benefit from this therapy [40]. Therefore, it would not be appropriate to use this strategy on all tumor types.…”

Section: Discussionmentioning

confidence: 99%

Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer

et al. 2019

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Background Synthetic lethal interactions (SLIs) that occur between gene pairs are exploited for cancer therapeutics. Studies in the model eukaryote yeast have identified ~ 550,000 negative genetic interactions that have been extensively studied, leading to characterization of novel pathways and gene functions. This resource can be used to predict SLIs that can be relevant to cancer therapeutics. Methods We used patient data to identify genes that are down-regulated in breast cancer. InParanoid orthology mapping was performed to identify yeast orthologs of the down-regulated genes and predict their corresponding SLIs in humans. The predicted network graphs were drawn with Cytoscape. CancerRXgene database was used to predict drug response. Results Harnessing the vast available knowledge of yeast genetics, we generated a Humanized Yeast Genetic Interaction Network (HYGIN) for 1009 human genes with 10,419 interactions. Through the addition of patient-data from The Cancer Genome Atlas (TCGA), we generated a breast cancer specific subnetwork. Specifically, by comparing 1009 genes in HYGIN to genes that were down-regulated in breast cancer, we identified 15 breast cancer genes with 130 potential SLIs. Interestingly, 32 of the 130 predicted SLIs occurred with FBXW7 , a well-known tumor suppressor that functions as a substrate-recognition protein within a SKP/CUL1/F-Box ubiquitin ligase complex for proteasome degradation. Efforts to validate these SLIs using chemical genetic data predicted that patients with loss of FBXW7 may respond to treatment with drugs like Selumitinib or Cabozantinib. Conclusions This study provides a patient-data driven interpretation of yeast SLI data. HYGIN represents a novel strategy to uncover therapeutically relevant cancer drug targets and the yeast SLI data offers a major opportunity to mine these interactions. Electronic supplementary material The online version of this article (10.1186/s12920-019-0554-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer

et al. 2019

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“…In addition to serving as a biomarker, ATM and BRCA1 are potential targets for anti-cancer therapy. Although not a direct drug target, cancer patients with BRCA1 mutation or homologous recombination deficiency (HRD) exhibit a good response to the treatment with PARP inhibitors, such as olaparib [ 24 ]. HRD can also be caused by defects in the genes involved in homologous recombination repair (HRR), such as ATM .…”

Section: Introductionmentioning

confidence: 99%

“…HRD can also be caused by defects in the genes involved in homologous recombination repair (HRR), such as ATM . Nowadays, regardless of histological types and anatomic sites, a lot of basket trials are ongoing to evaluate the efficacy of PARP inhibitors on the cancer patients with HRD phenotype, including ATM -deficient cancers and HNC [ 24 , 25 , 26 , 27 , 28 ]. Because ATM kinase plays a central role in initiating DDR, targeting ATM kinase may improve the efficacy of DNA-damaging-based treatment by suppressing DNA repair in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy

Wang

Lee

Tsai

et al. 2021

JPM

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ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and neck cancer (HNC) is not well characterized. Here, we examined the prognostic role of ATM and BRCA1 expression in two HNC cohorts with and without betel quid (BQ) exposure. The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Low expression of either ATM or BRCA1 was correlated with poor overall survival (OS) and was an independent prognostic factor in multivariate analysis (ATM HR: 1.895, p = 0.041; BRCA1 HR: 2.163, p = 0.040). The combination of ATM and BRCA1 expression states further improved on the prediction of OS (HR: 4.195, p = 0.001, both low vs. both high expression). Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy.

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“…We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages and ultimately lead to the development of treatments that can serve as part of a HIV cure strategy. As loss-of-function screens are being increasingly applied to understand disease mechanisms [ 26 ], we performed a genome-wide screen by employing a lentivirus-based library of shRNAs to identify novel gene targets, whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Herein, we report the screening of ~ 18,000 genes, and subsequent validation of 28 top hits in two viral models to identify four potential target genes, Cox7a2 , Znf484 , Cstf2t , and Cdk2 , whose loss-of-function induced apoptosis of HIV-infected macrophages.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening

et al. 2021

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Background Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. Methods We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student’s t-test from at least four independent experiments. Results We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. Conclusions We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.

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A Road Map to Personalizing Targeted Cancer Therapies Using Synthetic Lethality

Cited by 24 publications

References 138 publications

Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer

Humanized yeast genetic interaction mapping predicts synthetic lethal interactions of FBXW7 in breast cancer

Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy

Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening

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