ArticleCancer research2023
Topoisomerase 1 Inhibition in MYC-Driven Cancer Promotes Aberrant R-Loop Accumulation to Induce Synthetic Lethality.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 31 citations in OpenAlex.
- PUM3 is an essential suppressor of replication stress in homologous recombination deficient breast cancer.Nature communications · 2026Article
- MYC in Oncogenesis and Therapeutic Implications.MedComm · 2026Review
- MYC serine 62 phosphorylation promotes its association with DNA double-strand breaks to facilitate repair and cell survival under genotoxic stress.Genes & development · 2026Article
- Molecular mechanisms regulating cGAS/STING activation in health and disease.The Journal of clinical investigation · 2026Review
- EphB4 inhibition defines a druggable synthetic-lethal vulnerability in MYC-driven triple-negative breast cancer.Cell death & disease · 2026Article
- Multi-omics dissection of R-loop dynamics in tumorigenesis: From transcription-replication conflict to therapeutic targets.Molecular therapy. Oncology · 2026Review
- DNA-contact mutant p53 displaces BRCA2 from chromatin and drives R-loop-associated genome instability.Genome biology · 2026Article
- Deruxtecan-based antibody-drug-conjugates induce senescence in HER2-positive breast cancer.Scientific reports · 2026Article
- Application and prospect of breast cancer organoids model in the field of traditional Chinese medicine and natural compounds.Journal of translational medicine · 2026Review
- Inhibition of PRMT5 triggers synthetic lethality in ARID1A-deficient endometrial cancer by promoting aberrant R-loop accumulation.Molecular cancer · 2026Article
- The Roles of Topoisomerases in Transcriptional Regulation.International journal of molecular sciences · 2026Review
- Dynamic Supercoiling Sponsors Transcription Amplification by MYC.bioRxiv : the preprint server for biology · 2026Article
- Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance.Clinical and translational medicine · 2026Review
- Determinants of long-term response to patritumab deruxtecan in breast cancer patient-derived xenografts.NPJ precision oncology · 2025Article
- Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Topoisomerase I Inhibition in ETV4-overexpressed Non-Small Cell Lung Cancer Promotes Replication and Transcription Mediated R-Loop Accumulation and DNA Damage.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- CRISPR screening approaches in breast cancer research.Cancer metastasis reviews · 2025Review
- MYC: The Guardian of Its Own Chaos.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Senataxin prevents replicative stress induced by the Myc oncogene.Cell death & disease · 2025Article
- Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target.International journal of molecular sciences · 2025Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
MYC is a central regulator of gene transcription and is frequently dysregulated in human cancers. As targeting MYC directly is challenging, an alternative strategy is to identify specific proteins or processes required for MYC to function as a potent cancer driver that can be targeted to result in synthetic lethality. To identify potential targets in MYC-driven cancers, we performed a genome-wide CRISPR knockout screen using an isogenic pair of breast cancer cell lines in which MYC dysregulation is the switch from benign to transformed tumor growth. Proteins that regulate R-loops were identified as a potential class of synthetic lethal targets. Dysregulated MYC elevated global transcription and coincident R-loop accumulation. Topoisomerase 1 (TOP1), a regulator of R-loops by DNA topology, was validated to be a vulnerability in cells with high MYC activity. Genetic knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation compared with control cells, demonstrating synthetic lethality. Overexpression of RNaseH1, a riboendonuclease that specifically degrades R-loops, rescued the reduction in clonogenicity induced by TOP1 deficiency, demonstrating that this vulnerability is driven by aberrant R-loop accumulation. Genetic and pharmacologic TOP1 inhibition selectively reduced the fitness of MYC-transformed tumors in vivo. Finally, drug response to TOP1 inhibitors (i.e., topotecan) significantly correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids. Together, these results highlight TOP1 as a promising target for MYC-driven cancers. SIGNIFICANCE: CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.