ArticleClinical cancer research : an official journal of the American Association for Cancer Research2019
The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 56 citations in OpenAlex.
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- Molecular Determinants of Response and Rational Drug Combinations for Antibody-Drug Conjugates (ADCs) with Topoisomerase I (TOP1) Inhibitor Payloads.Journal of molecular biology · 2026Review
- Loss of Payload Sensitivity and Other Mechanisms of Resistance to T-DXd in HER2-Mutant NSCLC: Implications for Subsequent Responsiveness to HER2 TKIs.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 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
- High-grade serous ovarian cancer induced in different sites of origin in mice exemplifies diverse features of the human disease.iScience · 2026Article
- Co-expression of CD30 and SLFN11 serves as a dual biomarker for the treatment of cutaneous T-cell lymphoma.NAR cancer · 2025Article
- The evolving landscape of antibody-drug conjugates (ADCs) for treatment of prostate cancer.NPJ precision oncology · 2025Review
- Harnessing ExDNA for precision exatecan delivery in cancer: a novel antibody-drug conjugate approach.Molecular cancer · 2025Article
- A Difluorinated Derivative of ARC-111 Suppresses Intrahepatic Cholangiocarcinoma Growth via Targeting Topoisomerase I.ACS pharmacology & translational science · 2025Article
- SLFN11, far from being limited to responding to cancer DNA damage.Clinical and experimental medicine · 2025Review
- Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.Cancer chemotherapy and pharmacology · 2025Article
- Characterization of tumor prognosis and sensitive chemotherapy drugs based on cuproptosis-related gene signature in ovarian cancer.BMC women's health · 2025Article
- The present and future of the Cancer Dependency Map.Nature reviews. Cancer · 2025Review
- Phosphorylation-mediated conformational change regulates human SLFN11.Nature communications · 2024Article
- SLFN12 Expression Significantly Effects the Response to Chemotherapy Drugs in Triple-Negative Breast Cancer.Cancers · 2024Article
- Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors.Cancers · 2024Article
- PLX038A, a long-acting SN-38, penetrates the blood-tumor-brain-barrier, accumulates and releases SN-38 in brain tumors to increase survival of tumor bearing mice.Scientific reports · 2024Article
- Mechanisms of telomere maintenance and associated therapeutic vulnerabilities in malignant gliomas.Neuro-oncology · 2024Review
- Bone mimetic environments support engineering, propagation, and analysis of therapeutic response of patient-derived cells, ex vivo and in vivo.Acta biomaterialia · 2024Article
- Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
purposeIrinotecan and topotecan are used to treat a variety of different cancers. However, they have limitations, including chemical instability and severe side effects. To overcome these limitations, we developed the clinical indenoisoquinolines: LMP400 (indotecan), LMP776 (indimitecan), and LMP744. The purpose of the study is to build the molecular rationale for phase II clinical trials. EXPERIMENTAL
designCellMinerCDB (http://discover.nci.nih.gov/cellminercdb) was used to mine the cancer cell lines genomic databases. The causality of Schlafen11 (SLFN11) was validated in isogenic cell lines. Because topoisomerase I (TOP1)-mediated replication DNA damage is repaired by homologous recombination (HR), we tested the "synthetic lethality" of HR-deficient (HRD) cells. Survival and cell-cycle alterations were performed after drug treatments in isogenic DT40, DLD1, and OVCAR cell lines with BRCA1, BRCA2, or PALB2 deficiencies and in organoids cultured from prostate cancer patient-derived xenografts with BRCA2 loss. We also used an ovarian orthotopic allograft model with BRCA1 loss to validate the efficacy of LMP400 and olaparib combination.
resultsCellMinerCDB reveals that SLFN11, which kills cells undergoing replicative stress, is a dominant drug determinant to the clinical indenoisoquinolines. In addition, BRCA1-, BRCA2-, and PALB2-deficient cells were hypersensitive to the indenoisoquinolines. All 3 clinical indenoisoquinolines were also synergistic with olaparib, especially in the HRD cells. The synergy between LMP400 and olaparib was confirmed in the orthotopic allograft model harboring BRCA1 loss.
conclusionsOur results provide a rationale for molecularly designed clinical trials with the indenoisoquinolines as single agents and in combination with PARP inhibitors in HRD cancers expressing SLFN11.
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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.