Synthetic lethality in DNA repair network: A novel avenue in targeted cancer therapy and combination therapeutics

IUBMB Life, Год журнала: 2017, Номер 69(12), С. 929 - 937

Опубликована: Ноя. 23, 2017

Synthetic lethality refers to a lethal phenotype that results from the simultaneous disruptions of two genes, while disruption either gene alone is viable. Many DNA double strand break repair (DSBR) genes have synthetic relationships with oncogenes and tumor suppressor which can be exploited for targeted cancer therapy, an approach referred as combination therapy. double-strand breaks (DSBs) are one most toxic lesions cell repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). HR NHEJ particularly attractive targets therapy because these altered expression patterns in cells when compared normal genetic abnormalities selectively killing cells. Here, we review recent advances development small molecule inhibitors against induce address future directions clinical relevance this approach. © 2017 IUBMB Life, 69(12):929-937, 2017.

Язык: Английский

---

CRISPR–Cas9 a boon or bane: the bumpy road ahead to cancer therapeutics

Cancer Cell International, Год журнала: 2019, Номер 19(1)

Опубликована: Янв. 8, 2019

Genome editing allows for the precise manipulation of DNA sequences in a cell making this technology essential understanding gene function. CRISPR/Cas9 is targeted genome-editing platform derived from bacterial adaptive immune system and has been repurposed into tool. The RNA-guided endonuclease, Cas9 can be easily programmed to target new sites by altering its guide RNA sequence, easier, more efficient, scalable an indispensable tool biological research. This helped genetically engineer animal models understand disease mechanisms elucidate molecular details that exploited improved therapeutic outcomes. In review, we describe CRISPR-Cas9 gene-editing mechanism, CRISPR-screening methods, targeting CRISPR cancer immunotherapy. We also discuss ongoing clinical trials using tool, limitations might impede applicability future directions developing effective delivery systems may improve therapeutics.

Язык: Английский

---

PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics, Год журнала: 2019, Номер 9(2), С. 55 - 55

Опубликована: Май 18, 2019

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), one half all displaying defects important pathway recombination. Early studies have shown significant efficacy for PARP patients germline breast related antigens 1 and 2 (BRCA1/2) mutations. It has also become evident BRCA wild-type other benefit from this treatment. Companion deficiency (HRD) scores being developed to guide selection most likely inhibition. The choice which inhibitor is mainly based upon number prior therapies presence mutation or HRD. identification therapy view HRD biomarker assessments still challenging. aim review describe current evidence cancer, their mechanism action, outstanding issues, including rate long-term toxicities evolution resistance.

Язык: Английский

---

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Cancers, Год журнала: 2020, Номер 12(8), С. 2051 - 2051

Опубликована: Июль 25, 2020

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, instance an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, have evolved sophisticated damage response (DDR) pathways allow maintenance genome integrity. Recent years seen remarkable progress our understanding diverse DDR mechanisms, and, work, it has emerged metabolic regulation not only generates but also impacts on repair. Cancer show alteration coupled modifications metabolism, further emphasizing links between these two processes. Taken together, compelling findings indicate enzymes and metabolites represent key group factors within DDR. Here, we will compile current knowledge dynamic interplay DDR, specific focus cancer. We discuss how recently developed high-throughput technologies identification novel crosstalk which crucial importance better design efficient cancer treatments.

Язык: Английский

---

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

Frontiers in Cell and Developmental Biology, Год журнала: 2020, Номер 8

Опубликована: Апрель 2, 2020

The maintenance of genomic stability is crucial for species survival, and its failure closely associated with tumorigenesis. Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, germline defect any these genes can cause Fanconi's anemia, heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, predisposition to cancer. On the other hand, breast cancer susceptibility BRCA1 BRCA2, also known as FANCS FANCD1, respectively, are involved FA pathway; hence, researchers have studied association between pathway predisposition. Here, we mainly focused on systematically reviewed clinical mechanistic implications individuals abnormalities cancer, especially

Язык: Английский

---

Transcription Factors That Govern Development and Disease: An Achilles Heel in Cancer

Genes, Год журнала: 2019, Номер 10(10), С. 794 - 794

Опубликована: Окт. 12, 2019

Development requires the careful orchestration of several biological events in order to create any structure and, eventually, build an entire organism. On other hand, fate transformation terminally differentiated cells is a consequence erroneous development, and ultimately leads cancer. In this review, we elaborate how development cancer share processes, including molecular controls. Transcription factors (TF) are at helm both these among many others, evolutionarily conserved, ranging from yeast humans. Here, discuss four families TFs that play pivotal role have been studied extensively embryonic cancer-high mobility group box (HMG), GATA, paired (PAX) basic helix-loop-helix (bHLH) context their cancer, conservation across species. Finally, review as possible therapeutic targets for reflect on importance natural resistance against certain organisms, yielding knowledge regarding TF function biology.

Язык: Английский

---

Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

International Journal of Molecular Sciences, Год журнала: 2018, Номер 19(8), С. 2380 - 2380

Опубликована: Авг. 13, 2018

Type II endometrial carcinomas (ECs) are responsible for most cancer-related deaths due to their aggressive nature, late stage detection and high tolerance standard therapies. However, there no targeted therapies type ECs, they still treated the same way as clinically indolent easily treatable I ECs. Therefore, ECs in need of new treatment options. More recently, molecular analysis cancer revealed phosphorylation-dependent oncogenic signalling phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) mitogen-activated protein kinase (MAPK) pathways be frequently altered Consequently, clinical trials tested pharmacologic inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight common genetic alterations Additionally, reason why using had unsatisfying results what should changed future trial setups. Furthermore, argue that, besides kinases, phosphatases longer ignored trials, particularly where tumour suppressive phosphatase 2A (PP2A) is mutated. Lastly, discuss therapeutic potential PP2A (re)activation, possibly combination inhibitors.

Язык: Английский

---

Rare Genetic Diseases with Defects in DNA Repair: Opportunities and Challenges in Orphan Drug Development for Targeted Cancer Therapy

Cancers, Год журнала: 2018, Номер 10(9), С. 298 - 298

Опубликована: Сен. 1, 2018

A better understanding of mechanistic insights into genes and enzymes implicated in rare diseases provide a unique opportunity for orphan drug development. Advances made identification synthetic lethal relationships between disorder with oncogenes tumor suppressor have brought new anticancer therapeutic opportunities. Additionally, the rapid development small molecule inhibitors against that participate DNA damage response repair has been successful strategy targeted cancer therapeutics. Here, we discuss recent advances our how many disease promoting genome stability. We also summarize latest developments exploiting to uncover biological mechanisms identify interactions discovery are various stages preclinical clinical studies.

Язык: Английский

---

Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

Cancers, Год журнала: 2020, Номер 12(9), С. 2684 - 2684

Опубликована: Сен. 20, 2020

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved FA pathway are associated with development sporadic hematological solid malignancies. The key function orchestrate proteins repair interstrand cross-links (ICLs), prevent genomic instability replication stress. Recently, many studies have highlighted importance noncanonical pathways, such as mitochondria homeostasis, inflammation, virophagy, which act, some cases, independently DNA processes. Thus, primary defects mechanisms patients typically exacerbated an impairment other cytoprotective pathways that contribute multifaceted clinical phenotype this disease. In review, we summarize recent advances understanding pathogenesis FA, focus on cytosolic roles genes, discussing how they may cancer development, thus suggesting opportunities envisage novel therapeutic approaches.

Язык: Английский

---

The other side of the coin: protein deubiquitination by Ubiquitin-Specific Protease 1 in cancer progression and therapy

Future Medicinal Chemistry, Год журнала: 2025, Номер 17(3), С. 329 - 345

Опубликована: Янв. 17, 2025

Reversible protein ubiquitination is a crucial factor in cellular homeostasis, with Ubiquitin-Specific Protease 1 (USP1) serving as key deubiquitinase involved DNA damage response (DDR) and repair mechanisms cancer. While ubiquitin ligases have been extensively studied, research on the reverse process of ubiquitination, particularly involving USP1, remains relatively limited. USP1 overexpressed various cancers, influencing tumor initiation progression by regulating multiple associated proteins. Inhibiting effectively suppresses proliferation migration may help overcome resistance to cisplatin PARP inhibitors. As potential synthetic lethal target, demonstrates significant potential. This review highlights biological cancer progression, signaling pathways it regulates, latest advancements inhibitors, while also analyzing opportunities challenges targeting USP1. By adopting perspective "the other side coin," this aims underscore yet often overlooked role contrasting studied ligases, emphasizing its therapeutic treatment.

Язык: Английский

---