scholarly journals Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Jing Zhang ◽  
Li Jing ◽  
Subee Tan ◽  
Er-Ming Zeng ◽  
Yingbo Lin ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
High Throughput Screening ◽  
Synthetic Lethality ◽  
Gene Mutations ◽  
Primary Brain Tumor ◽  
Dna Double Strand Breaks ◽  
Synthetic Lethal ◽  
Oncogenic Mutation ◽  
Damage Repair ◽  
Genome Wide

Abstract Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are ‘coincidental’ treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs deficiency.

scholarly journals Uncovering cancer vulnerabilities by machine learning prediction of synthetic lethality

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Salvatore Benfatto ◽  
Özdemirhan Serçin ◽  
Francesca R. Dejure ◽  
Amir Abdollahi ◽  
Frank T. Zenke ◽  
...  
Keyword(s):  
Machine Learning ◽  
Cancer Genomics ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Interacting Protein ◽  
Synthetic Lethal ◽  
Damage Repair ◽  
Genome Wide ◽  
Machine Learning Approach ◽  
Transcriptomics Data

Abstract Background Synthetic lethality describes a genetic interaction between two perturbations, leading to cell death, whereas neither event alone has a significant effect on cell viability. This concept can be exploited to specifically target tumor cells. CRISPR viability screens have been widely employed to identify cancer vulnerabilities. However, an approach to systematically infer genetic interactions from viability screens is missing. Methods Here we describe PAn-canceR Inferred Synthetic lethalities (PARIS), a machine learning approach to identify cancer vulnerabilities. PARIS predicts synthetic lethal (SL) interactions by combining CRISPR viability screens with genomics and transcriptomics data across hundreds of cancer cell lines profiled within the Cancer Dependency Map. Results Using PARIS, we predicted 15 high confidence SL interactions within 549 DNA damage repair (DDR) genes. We show experimental validation of an SL interaction between the tumor suppressor CDKN2A, thymidine phosphorylase (TYMP) and the thymidylate synthase (TYMS), which may allow stratifying patients for treatment with TYMS inhibitors. Using genome-wide mapping of SL interactions for DDR genes, we unraveled a dependency between the aldehyde dehydrogenase ALDH2 and the BRCA-interacting protein BRIP1. Our results suggest BRIP1 as a potential therapeutic target in ~ 30% of all tumors, which express low levels of ALDH2. Conclusions PARIS is an unbiased, scalable and easy to adapt platform to identify SL interactions that should aid in improving cancer therapy with increased availability of cancer genomics data.

scholarly journals Cohesin mutations are synthetic lethal with stimulation of WNT signaling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chue Vin Chin ◽  
Jisha Antony ◽  
Sarada Ketharnathan ◽  
Anastasia Labudina ◽  
Gregory Gimenez ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Therapeutic Strategy ◽  
Synthetic Lethality ◽  
Mcf10a Cell ◽  
Synthetic Lethal ◽  
Deletion Mutations ◽  
Damage Repair ◽  
Genes Encoding ◽  
Mutant Cells ◽  
Gsk3 Inhibitor

Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21, and STAG2 and screened for synthetic lethality with 3009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin-mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunits stag2b and rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin-mutant cancers.

scholarly journals Cohesin mutations are synthetic lethal with stimulation of WNT signaling

2020 ◽  
Author(s):  
Chue Vin Chin ◽  
Jisha Antony ◽  
Sarada Ketharnathan ◽  
Gregory Gimenez ◽  
Kate M. Parsons ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Synthetic Lethality ◽  
Mcf10a Cell ◽  
Synthetic Lethal ◽  
Deletion Mutations ◽  
Damage Repair ◽  
Genes Encoding ◽  
Cohesin Subunit ◽  
Mutant Cells ◽  
Gsk3 Inhibitor

AbstractMutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21 and STAG2 and screened for synthetic lethality with 3,009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunit rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin mutant cancers.

scholarly journals Identifying chemogenetic interactions from CRISPR knockout screens with drugZ

2017 ◽  
Author(s):  
Medina Colic ◽  
Gang Wang ◽  
Michal Zimmermann ◽  
Keith Mascall ◽  
Megan McLaughlin ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Drug Efficacy ◽  
Chemical Compounds ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Synthetic Lethal ◽  
Drug Mechanism ◽  
Damage Repair ◽  
Synthetic Lethal Interactions ◽  
Additional Cell

AbstractChemogenetic profiling enables the identification of gene mutations that enhance or suppress the activity of chemical compounds. This knowledge provides insights into drug mechanism-of-action, genetic vulnerabilities, and resistance mechanisms, all of which may help stratify patient populations and improve drug efficacy. CRISPR-based screening enables sensitive detection of drug-gene interactions directly in human cells, but until recently has largely been used to screen only for resistance mechanisms. We present drugZ, an algorithm for identifying both synergistic and suppressor chemogenetic interactions from CRISPR screens. DrugZ identifies synthetic lethal interactions between PARP inhibitors and both known and novel members of the DNA damage repair pathway. Additionally, drugZ confirms KEAP1 loss as a resistance factor for ERK inhibitors in oncogenic KRAS backgrounds and identifies additional cell-specific mechanisms of drug resistance. The software is available at github.com/hart-lab/drugz.

scholarly journals A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3143
Author(s):  
Chaitra Rao ◽  
Dianna H. Huisman ◽  
Heidi M. Vieira ◽  
Danielle E. Frodyma ◽  
Beth K. Neilsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Natural Products ◽  
High Throughput ◽  
High Throughput Screening ◽  
Loss Of Function ◽  
Synthetic Lethal ◽  
Genome Wide ◽  
Pathway Activation ◽  
Kinase Suppressor Of Ras ◽  
Kinase Cascade

Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, revealing novel therapeutic targets. FUSION uses cell-based high-throughput screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA libraries to identify putative protein targets and mechanisms of action (MoA) for several previously undescribed natural products. We have used FUSION to screen for functional analogues to Kinase suppressor of Ras 1 (KSR1), a scaffold protein downstream of Ras in the Raf-MEK-ERK kinase cascade, and biologically validated several proteins with functional similarity to KSR1. FUSION incorporates bioinformatics analysis that may offer higher resolution of the endpoint readout than other screens which utilize Boolean outputs regarding a single pathway activation (i.e., synthetic lethal and cell proliferation). Challenges associated with FUSION and other high-content genome-wide screens include variation, batch effects, and controlling for potential off-target effects. In this review, we discuss the efficacy of FUSION to identify novel inhibitors and oncogene-induced changes that may be cancer cell-specific as well as several potential pitfalls within FUSION and best practices to avoid them.

scholarly journals P01.19 * A GENOME-WIDE RNAI SYNTHETIC LETHAL SCREEN FOR SENSITIZERS OF GLIOBLASTOMA MULTIFORME TO TEMOZOLOMIDE

2014 ◽  
Vol 16 (suppl 2) ◽  
pp. ii31-ii31
Author(s):  
T. A. Johannessen ◽  
A. Grudic ◽  
T. Sundstrom ◽  
J. K. Varughese ◽  
M. Lund-Johansen ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Synthetic Lethal ◽  
Genome Wide ◽  
A Genome

scholarly journals Identifying Novel Actionable Targets in Colon Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 579
Author(s):  
Maria Grazia Cerrito ◽  
Emanuela Grassilli
Keyword(s):  
Colon Cancer ◽  
High Throughput ◽  
High Throughput Screening ◽  
Drug Resistant ◽  
Synthetic Lethal ◽  
Oncogenic Mutations ◽  
Genome Wide ◽  
High Incidence ◽  
Personalized Approach ◽  
Near Future

Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed the identification of novel actionable targets and the development of the relative specific inhibitors to be used either to re-sensitize drug-resistant tumors (in combination with chemotherapy) or to be synthetic lethal for tumors with specific oncogenic mutations. Finally, high-throughput screening using FDA-approved libraries of “known” drugs uncovered new therapeutic applications of drugs (used alone or in combination) that have been in the clinic for decades for treating non-cancerous diseases (re-positioning or re-purposing approach). Thus, several novel actionable targets have been identified and some of them are already being tested in clinical trials, indicating that high-throughput approaches, especially those involving drug re-positioning, may lead in a near future to significant improvement of the therapy for colon cancer patients, especially in the context of a personalized approach, i.e., in defined subgroups of patients whose tumors carry certain mutations.

scholarly journals Epigenetic based synthetic lethal strategies in human cancers

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Aiai Gao ◽  
Mingzhou Guo
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Epigenetic Changes ◽  
Loss Of Function ◽  
Synthetic Lethal ◽  
Human Cancers ◽  
Damage Repair ◽  
Frequent Event ◽  
Cancer Types

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.

scholarly journals Epigenetic synthetic lethality approaches in cancer therapy

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Haoshen Yang ◽  
Wei Cui ◽  
Lihui Wang
Keyword(s):  
Fusion Proteins ◽  
High Throughput Screening ◽  
Malignant Tumors ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Synthetic Lethal ◽  
Epigenetic Regulators ◽  
Mutation Research ◽  
Synthetic Lethal Genes ◽  
Lethal Genes

Abstract The onset and development of malignant tumors are closely related to epigenetic modifications, and this has become a research hotspot. In recent years, a variety of epigenetic regulators have been discovered, and corresponding small molecule inhibitors have been developed, but their efficacy in solid tumors is generally poor. With the introduction of the first synthetic lethal drug (the PARP inhibitor olaparib in ovarian cancer with BRCA1 mutation), research into synthetic lethality has also become a hotspot. High-throughput screening with CRISPR-Cas9 and shRNA technology has revealed a large number of synthetic lethal pairs involving epigenetic-related synthetic lethal genes, such as those encoding SWI/SNF complex subunits, PRC2 complex subunits, SETD2, KMT2C, and MLL fusion proteins. In this review, we focus on epigenetic-related synthetic lethal mechanisms, including synthetic lethality between epigenetic mutations and epigenetic inhibitors, epigenetic mutations and non-epigenetic inhibitors, and oncogene mutations and epigenetic inhibitors.

scholarly journals Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 487 ◽  
Author(s):  
Isabella Faraoni ◽  
Grazia Graziani
Keyword(s):  
Synthetic Lethality ◽  
Metastatic Breast ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Wild Type ◽  
Dna Double Strand Breaks ◽  
Brca Mutations ◽  
Synthetic Lethal ◽  
Strand Breaks ◽  
Platinum Sensitive

Inhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors (PARPi; olaparib, rucaparib, niraparib and talazoparib) have been approved as monotherapies for BRCA-mutated or platinum-sensitive recurrent ovarian cancer and/or for BRCA-mutated HER2-negative metastatic breast cancer. PARPi therapeutic efficacy is higher against tumors harboring deleterious germline or somatic BRCA mutations than in BRCA wild-type tumors. BRCA mutations or intrinsic tumor sensitivity to platinum compounds are both regarded as indicators of deficiency in DSB repair by homologous recombination as well as of favorable response to PARPi. However, not all BRCA-mutated or platinum-responsive patients obtain clinical benefit from these agents. Conversely, a certain percentage of patients with wild-type BRCA or platinum-resistant tumors can still get benefit from PARPi. Thus, additional reliable markers need to be validated in clinical trials to select patients potentially eligible for PARPi-based therapies, in the absence of deleterious BRCA mutations or platinum sensitivity. In this review, we summarize the mechanisms of action of PARPi and the clinical evidence supporting their use as anticancer drugs as well as the additional synthetic lethal partners that might confer sensitivity to PARPi in patients with wild-type BRCA tumors.

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