ArticleMolecular cancer therapeutics2022
TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor.
Article in Molecular cancer therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 45 citations in OpenAlex.
- Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.Nature medicine · 2024Trial
- Molecular Determinants of Response and Rational Drug Combinations for Antibody-Drug Conjugates (ADCs) with Topoisomerase I (TOP1) Inhibitor Payloads.Journal of molecular biology · 2026Review
- Orthogonal Conjugation via Endoglycosidase and Microbial Transglutaminase Enables Efficient Synthesis of Dual-Payload Antibody-Drug Conjugates.ACS chemical biology · 2026Article
- Multi-omics dissection of R-loop dynamics in tumorigenesis: From transcription-replication conflict to therapeutic targets.Molecular therapy. Oncology · 2026Review
- Exatecan Payload-Based Antibody-Drug Conjugates with a Short Hydrophilic Cleavable Linker.ACS medicinal chemistry letters · 2026Article
- Topoisomerase I inhibitor antibody-drug conjugates in breast cancer: the relevance of the DNA damage response to resistance, response, and combination treatment strategies.Breast cancer research and treatment · 2026Review
- A Novel Dual-Payload ADC Platform Integrating Exatecan and Triptolide to Enhance Antitumor Efficacy and Overcome Resistance.Molecular cancer therapeutics · 2026Article
- DNA Damage and Nuclear Anaplasia Induced by Trastuzumab Deruxtecan in Cancer Cells with Variable HER2 Expression and Homologous Recombination Deficiency Status.Cancer research and treatment · 2026Article
- Targeting DNA Topoisomerase I for the Treatment of Cancer: Past, Present and Future.Journal of molecular biology · 2026Review
- Targeting Host Dependency Factors: A Paradigm Shift in Antiviral Strategy Against RNA Viruses.International journal of molecular sciences · 2025Review
- Preclinical Pharmacokinetic, Pharmacodynamic, and Safety Profile of OBI-992: A Novel TROP2-Targeted Antibody-Drug Conjugate.Molecular cancer therapeutics · 2025Article
- Hypoxia-responsive Exatecan prodrug liposomes co-delivered with IR808 for synergistic chemo-photodynamic therapy of breast cancer.International journal of pharmaceutics: X · 2025Article
- SLFN11, far from being limited to responding to cancer DNA damage.Clinical and experimental medicine · 2025Review
- HER2; p53 Co-mutated Cancers Show Increased Histone Acetylation and are Sensitive to Neratinib plus Trastuzumab Deruxtecan.bioRxiv : the preprint server for biology · 2025Article
- Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.Cancer chemotherapy and pharmacology · 2025Article
- Recent Advances in Augmenting the Therapeutic Efficacy of Peptide-Drug Conjugates.Journal of medicinal chemistry · 2025Review
- Evaluation of antigen agnostic anti-tumor activity and immune memory induced by CBX-15 (alphalexImmunotherapy · 2025Article
- Current progress and remaining challenges of peptide-drug conjugates (PDCs): next generation of antibody-drug conjugates (ADCs)?Journal of nanobiotechnology · 2025Review
- Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers.Gynecologic oncology · 2025Review
- Preclinical evaluation of a novel antibody-drug conjugate OBI-992 for Cancer therapy.Scientific reports · 2025Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to exatecan. We also show that exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide-exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.
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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.