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Cited by 60PARP inhibition in cancer therapyCancer therapeutics and mechanismsBRCA gene mutations in cancer

The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib

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Marzi, Laetitia, Szabova, Ludmila, Gordon, Melanie, Weaver Ohler, Zoe, Sharan, Shyam K., Beshiri, Michael L., Etemadi, Moudjib, Murai, Junko +2 more·2019·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-19-0419PMC PMC6801079

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Abstract

PURPOSE: Irinotecan 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 DESIGN: CellMinerCDB (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. RESULTS: CellMinerCDB 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. CONCLUSIONS: Our 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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  • TOPI inhibitor-induced SSBs require TDP1-mediated excision repair and homologous recombination pathways for repair.

    “TOPI inhibitor-induced SSBs require tyrosyl-DNA phosphodiesterase 1 (TDP1)-mediated excision repair and homologous recombination pathways for repair, so mCRPC tumors harboring HRD may exhibit increased sensitivity to TOPI inhibitor-carrying ADCs36,37.”

    From The evolving landscape of antibody-drug conjugates (ADCs) for treatment of prostate cancer (2025) · cites this paper as [37]

    The Discussion says TDP1 is recruited to excise trapped TOP1 cleavage complexes. The Introduction says homologous recombination repairs the double-strand breaks that can result when those complexes collide with DNA replication; it does not say homologous recombination repairs the single-strand breaks themselves. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • mCRPC tumors harboring HRD may exhibit increased sensitivity to TOPI inhibitor-carrying ADCs.

    “TOPI inhibitor-induced SSBs require tyrosyl-DNA phosphodiesterase 1 (TDP1)-mediated excision repair and homologous recombination pathways for repair, so mCRPC tumors harboring HRD may exhibit increased sensitivity to TOPI inhibitor-carrying ADCs36,37.”

    From The evolving landscape of antibody-drug conjugates (ADCs) for treatment of prostate cancer (2025) · cites this paper as [37]

    The Results section reports that a BRCA2-null organoid line derived from a castration-resistant prostate cancer xenograft was more sensitive to the TOP1 inhibitor LMP400 than a BRCA2-heterozygous line (page unavailable). This supports the proposed HRD–TOP1-inhibitor sensitivity, but the study tested the inhibitor directly, not a TOP1 inhibitor-carrying ADC or its effect in mCRPC tumors. (LLM, conf=0.88)

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Cited by

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Authors
Marzi, L., Szabova, L., Gordon, M., Weaver Ohler, Z., Sharan, S. K., Beshiri, M. L., Etemadi, M., Murai, J., Kelly, K., & Pommier, Y.
Affiliations
  • National Institutes of Health (US)
  • Frederick National Laboratory for Cancer Research (US)
  • 2Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research at the National Cancer Institute–Frederick, Frederick, Maryland.
Corresponding author
Pommier, Yves
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2019-10-15
Volume
25
Issue
20
Pages
6206-6216
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-19-0419
PMC
PMC6801079
OpenAlex
W2966931594
Cited by
60
References
2
Citations by year
2026: 6 · 2025: 10 · 2024: 12 · 2023: 7 · 2022: 8 · 2021: 9 · 2020: 8
FWCI
2.61
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Center for Cancer Research, the Intramural Program of the NCI (Z01-BC006161)
  • NIH (HHSN261200800001E)
Topics
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Keywords
indenoisoquinolines, topoisomerase I inhibitor, SLFN11, homologous recombination deficiency, synthetic lethality, olaparib, PARP inhibitors, BRCA1, BRCA2, PALB2, irinotecan, topotecan, drug synergy, prostate cancer, ovarian cancer, replicative stress, DNA repair
MeSH terms
Poly(ADP-ribose) Polymerase Inhibitors, Synthetic Lethal Mutations, Animals, Antineoplastic Combined Chemotherapy Protocols, Chickens, DNA Damage, DNA Topoisomerases, Type I, Drug Synergism, Female, Humans, Isoquinolines, Neoplasms, Nuclear Proteins, Phthalazines, Piperazines, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Benzodioxoles, Topoisomerase I Inhibitors, Recombinational DNA Repair

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