Article
Biochemistry & Molecular Biology
Russell Moser, Kay E. Gurley, Olga Nikolova, Guangrong Qin, Rashmi Joshi, Eduardo Mendez, Ilya Shmulevich, Amanda Ashley, Carla Grandori, Christopher J. Kemp
Summary: The study identified targetable dependencies in cancers carrying mutations in Ras and p53, and revealed differences in functional kinome profiles between Ras mutant cell lines, indicating rewiring of survival pathways caused by co-mutations.
Article
Oncology
Simonetta M. Leto, Martina Ferri, Francesco Sassi, Eugenia R. Zanella, Francesca Cottino, Valentina Vurchio, Irene Catalano, Alessandro Ferrero, Caterina C. Zingaretti, Caterina Marchio, Elena Grassi, Livio Trusolino, Andrea Bertotti
Summary: In this study, researchers aimed to find rational combinations to enhance the efficacy of the anti-EGFR antibody cetuximab in patients with RAS wild-type metastatic colorectal cancer (mCRC) by disrupting adaptive dependencies on antiapoptotic molecules. Through experiments conducted in patient-derived xenografts (PDX) and organoids (PDXO), they found that concomitant blockade of BCL-XL, an antiapoptotic protein, precipitated cell death and led to more pronounced tumor regressions in combination with cetuximab.
CLINICAL CANCER RESEARCH
(2023)
Article
Multidisciplinary Sciences
David Gallo, Jordan T. F. Young, Jimmy Fourtounis, Giovanni Martino, Alejandro Alvarez-Quilon, Cynthia Bernier, Nicole M. Duffy, Robert Papp, Anne Roulston, Rino Stocco, Janek Szychowski, Artur Veloso, Hunain Alam, Prasamit S. Baruah, Alexanne Bonneau Fortin, Julian Bowlan, Natasha Chaudhary, Jessica Desjardins, Evelyne Dietrich, Sara Fournier, Chloe Fugere-Desjardins, Theo Goullet de Rugy, Marie-Eve Leclaire, Bingcan Liu, Vivek Bhaskaran, Yael Mamane, Henrique Melo, Olivier Nicolas, Akul Singhania, Rachel K. Szilard, Jan Tkac, Shou Yun Yin, Stephen J. Morris, Michael Zinda, C. Gary Marshall, Daniel Durocher
Summary: Amplification of the CCNE1 locus on chromosome 19q12 is common in various tumor types, especially in high-grade serous ovarian cancer, uterine tumors, and gastro-esophageal cancers. The amplification of CCNE1 is associated with genome instability, high levels of cyclin E, and resistance to cytotoxic and targeted therapies. Through genome-scale CRISPR-Cas9-based synthetic lethality screens, it was discovered that increasing CCNE1 dosage creates vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. Inhibiting PKMYT1 through the development of RP-6306, an orally available and selective inhibitor, shows single-agent activity and durable tumor regressions when combined with gemcitabine in models of CCNE1 amplification. This treatment activates CDK1 selectively in CCNE1-overexpressing cells, promoting early mitosis in cells undergoing DNA synthesis, which is disrupted by CCNE1 overexpression. Thus, PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.
Article
Biology
Ilirjana Bajrami, Callum Walker, Dragomir B. Krastev, Daniel Weekes, Feifei Song, Andrew J. Wicks, John Alexander, Syed Haider, Rachel Brough, Stephen J. Pettitt, Andrew N. J. Tutt, Christopher J. Lord
Summary: The study investigated the synthetic lethality between BRCA gene defects and inhibition of two sirtuin genes, SIRT1 or SIRT6, which was associated with replication stress and increased PARylation. The authors demonstrated that this synthetic lethality could be reversed by genetic ablation of PARP1 or HPF1.
COMMUNICATIONS BIOLOGY
(2021)
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)
Article
Oncology
Julie A. Shields, Samuel R. Meier, Madhavi Bandi, Erin E. Mulkearns-Hubert, Nicole Hajdari, Maria Dam Ferdinez, Justin L. Engel, Daniel J. Silver, Binzhang Shen, Wenhai Zhang, Christopher G. Hubert, Kelly Mitchell, Sajina Shakya, Shan-Chuan Zhao, Alborz Bejnood, Minjie Zhang, Robert Tjin Tham Sjin, Erik Wilker, Justin D. Lathia, Jannik N. Andersen, Yingnan Chen, Fang Li, Barbara Weber, Alan Huang, Natasha Emmanuel
Summary: Synthetic lethality between paralog genes VRK1 and VRK2 plays a crucial role in treating VRK2-deficient glioblastoma.
Article
Cell Biology
Colin Stok, Stavroula Tsaridou, Nathalie van den Tempel, Marieke Everts, Elles Wierenga, Femke J. Bakker, Yannick Kok, Ines Teles Alves, Lucas T. Jae, Maximilian W. D. Raas, Pim J. Huis in't Veld, H. Rudolf de Boer, Arkajyoti Bhattacharya, Eleftheria Karanika, Harry Warner, Mengting Chen, Bert van de Kooij, Julien Dessapt, Lars ter Morsche, Polina Perepelkina, Amelie Fradet-Turcotte, Victor Guryev, Eelco C. Tromer, Kok-Lung Chan, Rudolf S. N. Fehrmann, Marcel A. T. M. van Vugt
Summary: Joint DNA molecules are byproducts of DNA replication and repair. Persistent joint molecules form ultrafine DNA bridges (UFBs) in mitosis, affecting sister chromatid separation. PICH plays a central role in resolving UFBs. A loss-of-function screen reveals that FIRRM interacts with and stabilizes FIGNL1, and their inactivation leads to UFB formation, RAD51 accumulation, impaired replication fork dynamics, and genome instability. These findings suggest that dysregulation of RAD51 dynamics at replication forks due to FIRRM and FIGNL1 inactivation results in persistent DNA lesions and a dependence on PICH for cell survival.
Article
Chemistry, Analytical
Xiaogang Lu, Zixuan Zhang, Haibo Liu, Hui Tang, Runli Gao, Chengxin Pei, Hongmei Wang, Junhua Xiao
Summary: This study utilized gas chromatography and mass spectrometry (GC-MS) to track the production of tabun by analyzing synthetic DMPADC, successfully discriminating and classifying synthetic samples through the establishment of a model.
Article
Multidisciplinary Sciences
Mehdi Dehghan Manshadi, Payam Setoodeh, Habil Zare
Summary: This article introduces a new Rapid-SL method for efficient and targeted identification of synthetic lethals (SLs). The method has the advantages of enumerating all SLs, shorter runtime, embarrassingly parallel computations, and targeted identification of SLs. By investigating a small portion of the search space, high-order SLs can be effectively discovered.
SCIENTIFIC REPORTS
(2022)
Review
Oncology
Colm J. Ryan, Ishan Mehta, Narod Kebabci, David J. Adams
Summary: Synthetic lethal interactions, especially between paralogs, can be exploited for cancer targeted therapeutics development and existing small-molecule drugs may also target multiple paralogs simultaneously. The identification of these interactions is crucial for drug development.
Review
Oncology
Arindam Datta, Srijita Dhar, Sanket Awate, Robert M. Brosh
Summary: DNA helicases play crucial roles in genome stability and cancer cells, with potential for synthetic lethality through genetic interactions with other proteins.
Article
Medicine, Research & Experimental
Jie Li, Jingyi Lu, Manman Xu, Shiyu Yang, Tiantian Yu, Cuimiao Zheng, Xi Huang, Yuwen Pan, Yangyang Chen, Junming Long, Chunyu Zhang, Hua Huang, Qingyuan Dai, Bo Li, Wei Wang, Shuzhong Yao, Chaoyun Pan
Summary: Through an RNAi screen, targeting ODF2L was found to be synthetically lethal with WEE1 kinase inhibition in epithelial ovarian cancer (EOC) cells. Knockdown of ODF2L increased the sensitivity of EOC cells to WEE1 inhibitor AZD1775 by promoting DNA damage accumulation. Clinically, upregulation of ODF2L was correlated with CDK1 activity, DNA damage levels, and sensitivity to WEE1 inhibition in patient-derived EOC cells.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Oncology
Kseniya Glinkina, Arwin Groenewoud, Amina F. A. S. Teunisse, B. Ewa Snaar-Jagalska, Aart G. Jochemsen
Summary: In this study, we used CRISPR-Cas9 synthetic lethality screening to identify molecular targets that can enhance the effect of everolimus in uveal melanoma cells. IGF1R and PRKDC were among the hits, and their synergy with everolimus was confirmed. The dual DNA-PKcs/mTOR inhibitor CC-115 showed significant activity in an in vivo model.
Article
Health Care Sciences & Services
Grace S. Shieh
Summary: This article reviews the applications of the synthetic lethal (SL) concept in translational cancer medicine over the past five years. It discusses the use of SL concept in drug combinations to overcome tumor resistance, the identification of prognostic and predictive biomarkers using synthetic lethality, the application of SL interactions in stratifying patients for targeted and immunotherapy, as well as the challenges and future directions in this field.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Multidisciplinary Sciences
Thibault Houles, Genevieve Lavoie, Sami Nourreddine, Winnie Cheung, Eric Vaillancourt-Jean, Celia M. Guerin, Mathieu Bouttier, Benoit Grondin, Sichun Lin, Marc K. Saba-El-Leil, Stephane Angers, Sylvain Meloche, Philippe P. Roux
Summary: The study reveals the regulation of CDK12 activity by the RAS/MAPK pathway in melanoma, highlighting the potential of CDK12 inhibitors in combination with other pathways to suppress melanoma growth. Increased CDK12 activity in melanoma cells leads to higher expression of DNA repair genes, while its inhibition promotes the expression of genes associated with growth promotion.
NATURE COMMUNICATIONS
(2022)
