title: Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.
abstract: Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors.
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Institut Universitaire de Cancérologie (IUC), Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.|Departamento de Biofísica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lima
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Institut Universitaire de Cancérologie (IUC), Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.
authors.forename: Hana
authors.initials: H
authors.lastname: Bouzid
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Institut Universitaire de Cancérologie (IUC), Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.|Medical Oncology Department, Hospital Tenon, Public Assistance Hospitals of Paris (AP-HP), Alliance Pour la Recherche en Cancérologie (APREC), Paris, France.
authors.forename: Daniele G
authors.initials: DG
authors.lastname: Soares
authors.affiliation: Medical Oncology Department, Hospital Tenon, Public Assistance Hospitals of Paris (AP-HP), Alliance Pour la Recherche en Cancérologie (APREC), Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Selle
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Institut Universitaire de Cancérologie (IUC), Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Morel
authors.affiliation: Cell Biology Department, PharmaMar, Poligono Industrial La Mina, Colmenar Viejo, Madrid, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.affiliation: Departamento de Biofísica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Instituto de Biotecnologia, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil.
authors.forename: João A P
authors.initials: JA
authors.lastname: Henriques
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Institut Universitaire de Cancérologie (IUC), Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Institut Universitaire de Cancérologie (IUC), Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Escargueil
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors*; D002243:Carbolines / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D059767:Recombinational DNA Repair / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002243:Carbolines; D004149:Dioxoles; D006576:Heterocyclic Compounds, 4 or More Rings; C568606:PM 01183; D044005:Tetrahydroisoquinolines; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000077606:Trabectedin
keywords: DNA alkylators; DNA double strand breaks; DNA replication; checkpoint abrogators; homologous recombination