Article
Multidisciplinary Sciences
Biyu Zhang, Chen Tang, Yanli Yao, Xiaohan Chen, Chi Zhou, Zhiting Wei, Feiyang Xing, Lan Chen, Xiang Cai, Zhiyuan Zhang, Shuyang Sun, Qi Liu
Summary: Synthetic lethality is becoming an important cancer therapeutic paradigm, but comprehensive selective treatment opportunities for various tumors have not been fully explored. The Synthetic Lethality Knowledge Graph (SLKG) integrates data on different tumors, drugs, and drug targets to provide therapy options for synthetic lethality and synthetic dosage lethality, prioritizing the identification of repurposable drug candidates and combinations with supporting evidence for novel tumor therapy discovery.
NATURE COMMUNICATIONS
(2021)
Letter
Oncology
M. Spalato-Ceruso, A. Laroche-Clary, R. Perret, Y. Valverde, V Chaire, Marie-Alix Derieppe, V. Velasco, A. Bourdon, A. Italiano
Summary: Soft-tissue sarcoma (STS) is a rare and heterogeneous group of tumors with limited treatment options and high fatality rates. However, targeting ATM signaling network genes has been found to overcome resistance to ATR inhibition, as demonstrated by our CRISPR/Cas9 knockout models. Furthermore, the combination of ATM inhibitor AZD0156 and ATR inhibitor AZD6738 has shown synergistic effects, significantly inhibiting STS growth in vitro and inducing higher levels of DNA damage.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2023)
Review
Oncology
Marta Roman, Elizabeth Hwang, E. Alejandro Sweet-Cordero
Summary: This article discusses the latest advancements in identifying synthetic lethal interactions in KRAS-mutant cancers and highlights the application of functional genomics and model development. These advancements provide hope for the discovery of new clinical treatments.
Review
Biochemistry & Molecular Biology
Yuko Kinowaki, Towako Taguchi, Iichiroh Onishi, Susumu Kirimura, Masanobu Kitagawa, Kouhei Yamamoto
Summary: Ferroptosis is a type of iron-dependent, non-apoptotic cell death that sensitizes drug-resistant tumors and cancer stem cells. Synthetic lethal strategies, targeting mechanisms not directly addressed by conventional therapies, show potential for specific malignant cells with low toxicity and possible new drug combinations. The research focuses on exploring ferroptosis-related molecules and synthetic lethality for potential therapeutic targets.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemical Research Methods
Jing Wang, Qinglong Zhang, Junshan Han, Yanpeng Zhao, Caiyun Zhao, Bowei Yan, Chong Dai, Lianlian Wu, Yuqi Wen, Yixin Zhang, Dongjin Leng, Zhongming Wang, Xiaoxi Yang, Song He, Xiaochen Bo
Summary: This review article discusses the recent applications of computational methods in synthetic lethality (SL) prediction. It introduces the concept and screening methods of SL, summarizes various SL-related data resources, and provides an overview of computational methods including statistical-based methods, network-based methods, classical machine learning methods, and deep learning methods for SL prediction. The article also highlights the use of negative sampling methods in these models. Representative tools for SL prediction are introduced, and the challenges and future work for SL prediction are discussed.
BRIEFINGS IN BIOINFORMATICS
(2022)
Review
Oncology
Chen Wang, Hui Fang, Jiawei Zhang, Ying Gu
Summary: Synthetic lethal screening is a promising method for identifying novel drug targets, particularly for targeting undruggable proteins like c-Myc. Inhibiting important functional nodes related to c-Myc in non-oncogene addicted networks may have catastrophic effects on tumor cells but not on normal cells. This research field has made progress in identifying these functional nodes and holds great potential for potent tumor treatment.
FRONTIERS OF MEDICINE
(2021)
Article
Medicine, Research & Experimental
Chen Yang, Yuchen Guo, Ruolan Qian, Yiwen Huang, Linmeng Zhang, Jun Wang, Xiaowen Huang, Zhicheng Liu, Wenxin Qin, Cun Wang, Huimin Chen, Xuhui Ma, Dayong Zhang
Summary: Through the analysis of synthetic lethality interactions, potential therapeutic targets in liver cancer were identified, suggesting a novel personalized treatment approach. This may offer more effective treatment options for patients with liver cancer.
Review
Cell Biology
Jayaprakash Mandal, Prativa Mandal, Tian-Li Wang, Ie-Ming Shih
Summary: Chromatin remodeling is a crucial cellular process that plays a key role in cell function. ARID1A is the most commonly mutated chromatin remodeling gene and is closely associated with cancer development. Deficiency in ARID1A leads to tumor progression and dissemination. PARP inhibitors can be used as a therapeutic approach for ARID1A-mutated tumors.
JOURNAL OF BIOMEDICAL SCIENCE
(2022)
Article
Biochemical Research Methods
Omer Sabary, Yoav Orlev, Roy Shafir, Leon Anavy, Eitan Yaakobi, Zohar Yakhini
Summary: The study introduced a novel analysis tool called SOLQC for fast and comprehensive analysis of synthetic oligo libraries. The tool provides statistical information and generates graphical reports in a flexible format. The authors demonstrated the application of the tool and discussed the potential benefits of the analysis components.
Review
Biochemistry & Molecular Biology
Parasvi S. Patel, Arash Algouneh, Razq Hakem
Summary: The principle of synthetic lethality, aiming at disrupting two genes to eliminate tumors, particularly in BRCA1/2-mutated cancers, has been a focus in cancer research. Although PARP inhibitors have shown clinical success in certain cases, resistance remains an issue and the exploration of alternative targets is crucial for future therapies. Various synthetic lethal interactors of BRCA1/2 have been identified, providing potential avenues for the development of new targeted therapies.
Article
Cell Biology
Mingchao Wang, Xiaojuan Ran, Wendy Leung, Ajinkya Kawale, Sneha Saxena, Jian Ouyang, Parasvi S. Patel, Yuting Dong, Tao Yin, Jian Shu, Robert T. Manguso, Li Lan, Xiao-Fan Wang, Michael S. Lawrence, Lee Zou
Summary: This study demonstrates that the inhibition of ATR kinase selectively kills MMR-d cancer cells by inducing DNA damage, activating cGAS signaling, and promoting antitumor immunity. The combination of ATRi and anti-PD-1 antibody shows enhanced efficacy against MMR-d tumors.
GENES & DEVELOPMENT
(2023)
Review
Oncology
Yucui Xin, Yingsheng Zhang
Summary: Tumor cells can be specifically targeted by disrupting the function of the other genes in synthetic lethality (SL) settings, while leaving normal cells unharmed. Paralogs, homologous genes that have diverged from each other, are ideal SL targets in tumor cells due to their frequent homozygous loss. However, the unclear mechanisms of targeting these gene pairs and the difficulty in finding specific inhibitors hinder further clinical development.
FRONTIERS IN ONCOLOGY
(2023)
Review
Oncology
Ananna Bhadra Arna, Hardikkumar Patel, Ravi Shankar Singh, Frederick S. Vizeacoumar, Anthony Kusalik, Andrew Freywald, Franco J. Vizeacoumar, Yuliang Wu
Summary: DEAD/H-box helicases play important roles in various aspects of RNA metabolism and their dysregulation is associated with cancer. Synthetic lethality (SL) and synthetic dosage lethality (SDL) approaches, which exploit genetic interactions among cancer-related genes, have shown promise in cancer research. This review analyzes the gene expression of DEAD/H-box helicases in different cancer types and discusses the potential therapeutic applications of their SL/SDL interactions. The latest developments in clinical applications and challenges in targeting DEAD/H-box helicases for drug discovery are also discussed.
FRONTIERS IN ONCOLOGY
(2023)
Review
Pharmacology & Pharmacy
Laura Guantay, Cintia Garro, Sebastian Siri, Maria Florencia Pansa, Sonja Ghidelli-Disse, Natalia Paviolo, Ana Racca, Viviana Nicotra, Caius Radu, Jose Luis Bocco, Rosana Felice, Keith H. Jansson, Katja Remlinger, Alejandro Amador, Euan Stronach, Kevin Coleman, Marcel Muelbaier, Gerard Drewes, Isro Gloger, Kevin Madauss, Manuela Garcia, Vanesa Gottifredi, Gaston Soria
Summary: The plant-derived compound Solanocapsine was found to selectively induce Synthetic Lethality (SL) in BRCA2-deficient cells. The nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) was identified as the target responsible for Solanocapsine's SL induction. Inhibition of dCK with the specific inhibitor DI-87 also induced SL in multiple BRCA2-deficient models, highlighting dCK as a promising target for future therapeutic alternatives to PARP inhibitors.
DRUG RESISTANCE UPDATES
(2023)
Review
Genetics & Heredity
Malgorzata Drzewiecka, Gabriela Barszczewska-Pietraszek, Piotr Czarny, Tomasz Skorski, Tomasz Sliwinski
Summary: Research studies on synthetic lethality in human cells aim to develop effective and safe anti-cancer chemotherapy. DNA repair factors, especially those involved in double-strand break repair, are the primary targets for inducing the synthetic lethality effect. Inhibition of RAD52 and/or PARP1 has shown promise as a potential target for inducing synthetic lethality in tumor cells with deficiencies in the canonical repair pathways. However, resistance to PARP1 inhibitors poses a major obstacle to successful treatment protocols. DNA polymerase theta (Pol theta) plays a key role in an alternative DSB repair pathway and its inhibition holds potential for inducing synthetic lethality in tumors with homologous recombination repair deficiencies.