scholarly journals Loss of the abasic site sensor HMCES is synthetic lethal with the activity of the APOBEC3A cytosine deaminase in cancer cells

PLoS Biology ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. e3001176
Author(s):  
Josep Biayna ◽  
Isabel Garcia-Cao ◽  
Miguel M. Álvarez ◽  
Marina Salvadores ◽  
Jose Espinosa-Carrasco ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Synthetic Lethality ◽  
Strong Association ◽  
Cytosine Deaminase ◽  
Abasic Site ◽  
Selective Treatment ◽  
Synthetic Lethal ◽  
Checkpoint Kinases ◽  
Abasic Sites ◽  
Central Protein

Analysis of cancer mutagenic signatures provides information about the origin of mutations and can inform the use of clinical therapies, including immunotherapy. In particular, APOBEC3A (A3A) has emerged as a major driver of mutagenesis in cancer cells, and its expression results in DNA damage and susceptibility to treatment with inhibitors of the ATR and CHK1 checkpoint kinases. Here, we report the implementation of CRISPR/Cas-9 genetic screening to identify susceptibilities of multiple A3A-expressing lung adenocarcinoma (LUAD) cell lines. We identify HMCES, a protein recently linked to the protection of abasic sites, as a central protein for the tolerance of A3A expression. HMCES depletion results in synthetic lethality with A3A expression preferentially in a TP53-mutant background. Analysis of previous screening data reveals a strong association between A3A mutational signatures and sensitivity to HMCES loss and indicates that HMCES is specialized in protecting against a narrow spectrum of DNA damaging agents in addition to A3A. We experimentally show that both HMCES disruption and A3A expression increase susceptibility of cancer cells to ionizing radiation (IR), oxidative stress, and ATR inhibition, strategies that are often applied in tumor therapies. Overall, our results suggest that HMCES is an attractive target for selective treatment of A3A-expressing tumors.

scholarly journals Loss of HMCES is synthetic lethal with APOBEC activity in cancer cells

2021 ◽  
Author(s):  
Josep Biayna ◽  
Isabel Garcia-Cao ◽  
Miguel M. Álvarez ◽  
Marina Salvadores ◽  
Jose Espinosa-Carrasco ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Synthetic Lethality ◽  
Strong Association ◽  
Selective Treatment ◽  
Mutational Signatures ◽  
Synthetic Lethal ◽  
Checkpoint Kinases ◽  
Abasic Sites ◽  
Dna Damaging Agents ◽  
Central Protein

AbstractAnalysis of cancer mutagenic signatures provides information about the origin of mutations and can inform the use of clinical therapies, including immunotherapy. In particular, APOBEC3A (A3A) has emerged as a major driver of mutagenesis in cancer cells and its expression results in DNA damage and susceptibility to treatment with inhibitors of the ATR and CHK1 checkpoint kinases. Here we report the implementation of CRISPR/Cas9 genetic screening to identify susceptibilities of multiple A3A-expressing lung adenocarcinoma cell lines. We identify HMCES, a protein recently linked to the protection of abasic sites, as a central protein for the tolerance of A3A expression. HMCES depletion results in synthetic lethality with A3A expression specifically in a TP53-mutant background. Analysis of previous screening data reveals a strong association between A3A mutational signatures and sensitivity to HMCES loss and indicates that HMCES is specialized in protecting against a narrow spectrum of DNA damaging agents in addition to A3A. We experimentally show that both HMCES disruption and A3A expression increase susceptibility of cancer cells to ionizing radiation, oxidative stress and ATR inhibition; strategies that are often applied in tumor therapies. Overall, our results suggest that HMCES is an attractive target for selective treatment of A3A expressing tumors.

scholarly journals Identifying collateral and synthetic lethal vulnerabilities within the DNA-damage response

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Pietro Pinoli ◽  
Sriganesh Srihari ◽  
Limsoon Wong ◽  
Stefano Ceri
Keyword(s):  
Cancer Cells ◽  
Synthetic Lethality ◽  
Mutual Exclusion ◽  
Copy Number Variations ◽  
Cancer Therapies ◽  
Synthetic Lethal ◽  
Gene Pairs ◽  
Synthetically Lethal ◽  
Highly Correlated ◽  
Exclusive Group

Abstract Background A pair of genes is defined as synthetically lethal if defects on both cause the death of the cell but a defect in only one of the two is compatible with cell viability. Ideally, if A and B are two synthetic lethal genes, inhibiting B should kill cancer cells with a defect on A, and should have no effects on normal cells. Thus, synthetic lethality can be exploited for highly selective cancer therapies, which need to exploit differences between normal and cancer cells. Results In this paper, we present a new method for predicting synthetic lethal (SL) gene pairs. As neighbouring genes in the genome have highly correlated profiles of copy number variations (CNAs), our method clusters proximal genes with a similar CNA profile, then predicts mutually exclusive group pairs, and finally identifies the SL gene pairs within each group pairs. For mutual-exclusion testing we use a graph-based method which takes into account the mutation frequencies of different subjects and genes. We use two different methods for selecting the pair of SL genes; the first is based on the gene essentiality measured in various conditions by means of the “Gene Activity Ranking Profile” GARP score; the second leverages the annotations of gene to biological pathways. Conclusions This method is unique among current SL prediction approaches, it reduces false-positive SL predictions compared to previous methods, and it allows establishing explicit collateral lethality relationship of gene pairs within mutually exclusive group pairs.

scholarly journals New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors

2021 ◽  
Vol 22 (24) ◽  
pp. 13324
Author(s):  
Watson P. Folk ◽  
Alpana Kumari ◽  
Tetsushi Iwasaki ◽  
Erica K. Cassimere ◽  
Slovénie Pyndiah ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Synthetic Lethality ◽  
Lethal Effect ◽  
Parp Inhibition ◽  
Synthetic Lethal ◽  
Cisplatin Sensitivity ◽  
Platinum Refractory

The pro-apoptotic tumor suppressor BIN1 inhibits the activities of the neoplastic transcription factor MYC, poly (ADP-ribose) polymerase-1 (PARP1), and ATM Ser/Thr kinase (ATM) by separate mechanisms. Although BIN1 deficits increase cancer-cell resistance to DNA-damaging chemotherapeutics, such as cisplatin, it is not fully understood when BIN1 deficiency occurs and how it provokes cisplatin resistance. Here, we report that the coordinated actions of MYC, PARP1, and ATM assist cancer cells in acquiring cisplatin resistance by BIN1 deficits. Forced BIN1 depletion compromised cisplatin sensitivity irrespective of Ser15-phosphorylated, pro-apoptotic TP53 tumor suppressor. The BIN1 deficit facilitated ATM to phosphorylate the DNA-damage-response (DDR) effectors, including MDC1. Consequently, another DDR protein, RNF8, bound to ATM-phosphorylated MDC1 and protected MDC1 from caspase-3-dependent proteolytic cleavage to hinder cisplatin sensitivity. Of note, long-term and repeated exposure to cisplatin naturally recapitulated the BIN1 loss and accompanying RNF8-dependent cisplatin resistance. Simultaneously, endogenous MYC was remarkably activated by PARP1, thereby repressing the BIN1 promoter, whereas PARP inhibition abolished the hyperactivated MYC-dependent BIN1 suppression and restored cisplatin sensitivity. Since the BIN1 gene rarely mutates in human cancers, our results suggest that simultaneous inhibition of PARP1 and ATM provokes a new BRCAness-independent synthetic lethal effect and ultimately re-establishes cisplatin sensitivity even in platinum-refractory cancer cells.

scholarly journals Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality

2019 ◽  
Vol 24 (5) ◽  
pp. 548-562
Author(s):  
Dedrick Soon Seng Song ◽  
Sze Wei Leong ◽  
Kwok Wen Ng ◽  
Faridah Abas ◽  
Khozirah Shaari ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Treatment Options ◽  
Cancer Cell Lines ◽  
Selective Toxicity ◽  
Synthetic Lethal ◽  
Dna Mismatch

DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency.

A (synthetic) lethal weapon for cancer

2018 ◽  
Vol 10 (437) ◽  
pp. eaat4477
Author(s):  
Amaia Lujambio
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Synthetic Lethality ◽  
Breast Cancer Patients ◽  
Selective Treatment ◽  
Synthetic Lethal ◽  
E Cadherin

ROS1 inhibition in E-cadherin–deficient tumors leads to synthetic lethality, which could be exploited for the selective treatment of breast cancer patients.

scholarly journals RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1561 ◽  
Author(s):  
Toma ◽  
Sullivan-Reed ◽  
Śliwiński ◽  
Skorski
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Synthetic Lethality ◽  
Lethal Effect ◽  
Drug Induced ◽  
Synthetic Lethal ◽  
Repair Mechanisms ◽  
Cancer Tumor

Alterations in DNA repair systems play a key role in the induction and progression of cancer. Tumor-specific defects in DNA repair mechanisms and activation of alternative repair routes create the opportunity to employ a phenomenon called “synthetic lethality” to eliminate cancer cells. Targeting the backup pathways may amplify endogenous and drug-induced DNA damage and lead to specific eradication of cancer cells. So far, the synthetic lethal interaction between BRCA1/2 and PARP1 has been successfully applied as an anticancer treatment. Although PARP1 constitutes a promising target in the treatment of tumors harboring deficiencies in BRCA1/2—mediated homologous recombination (HR), some tumor cells survive, resulting in disease relapse. It has been suggested that alternative RAD52-mediated HR can protect BRCA1/2-deficient cells from the accumulation of DNA damage and the synthetic lethal effect of PARPi. Thus, simultaneous inhibition of RAD52 and PARP1 might result in a robust dual synthetic lethality, effectively eradicating BRCA1/2-deficient tumor cells. In this review, we will discuss the role of RAD52 and its potential application in synthetic lethality-based anticancer therapies.

scholarly journals Synthetic Lethal Activity of Benzophenanthridine Alkaloids From Zanthoxylum coco Against BRCA1-Deficient Cancer Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Iris A. García ◽  
Maria Florencia Pansa ◽  
Adriana Del Valle Pacciaroni ◽  
Manuela E. García ◽  
Maria Laura Gonzalez ◽  
...  
Keyword(s):  
Cancer Cells ◽  
High Throughput Screening ◽  
Synthetic Lethality ◽  
Underlying Mechanism ◽  
Native Plant ◽  
Benzophenanthridine Alkaloids ◽  
Native Plant Species ◽  
Synthetic Lethal ◽  
Cytotoxic Compounds ◽  
Nanomolar Range

Several plants from South America show strong antitumoral properties based on anti-proliferative and/or pro-apoptotic activities. In this work we aimed to identify selective cytotoxic compounds that target BRCA1-deficient cancer cells by Synthetic Lethality (SL) induction. Using a high-throughput screening technology developed in our laboratory, we analyzed a collection of extracts from 46 native plant species from Argentina using a wide dose-response scheme. A highly selective SL-induction capacity was found in an alkaloidal extract from Zanthoxylum coco (Fam. Rutaceae). Bio-guided fractionation coupled to HPLC led to the identification of active benzophenanthridine alkaloids. The most potent SL activity was found with the compound oxynitidine, which showed a remarkably low relative abundance in the active fractions. Further validation experiments were performed using the commercially available and closely related analog nitidine, which showed SL-induction activity against various BRCA1-deficient cell lines with different genetic backgrounds, even in the nanomolar range. Exploration of the underlying mechanism of action using BRCA1-KO cells revealed AKT and topoisomerases as the potential targets responsible of nitidine-triggered SL-induction. Taken together, our findings expose an unforeseen therapeutic activity of alkaloids from Zanthoxylum-spp. that position them as novel lead molecules for drug discovery.

Sign in / Sign up

Export Citation Format

Share Document