Oncotarget

Research Papers:

Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair

Michelle Lima _, Hana Bouzid, Daniele G. Soares, Frédéric Selle, Claire Morel, Carlos M. Galmarini, João A. P. Henriques, Annette K. Larsen and Alexandre E. Escargueil

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Oncotarget. 2016; 7:25885-25901. https://doi.org/10.18632/oncotarget.8292

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Abstract

Michelle Lima1,2,*, Hana Bouzid1,*, Daniele G. Soares1,3, Frédéric Selle3, Claire Morel1, Carlos M. Galmarini4, João A. P. Henriques2,5, Annette K. Larsen1, Alexandre E. Escargueil1

1Cancer 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

2Departamento de Biofísica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

3Medical Oncology Department, Hospital Tenon, Public Assistance Hospitals of Paris (AP-HP), Alliance Pour la Recherche en Cancérologie (APREC), Paris, France

4Cell Biology Department, PharmaMar, Poligono Industrial La Mina, Colmenar Viejo, Madrid, Spain

5Instituto de Biotecnologia, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil

*These authors contributed equally to this work

Correspondence to:

Alexandre E. Escargueil, email: [email protected]

Keywords: DNA double strand breaks, DNA alkylators, DNA replication, homologous recombination, checkpoint abrogators

Received: November 29, 2015    Accepted: March 04, 2016    Published: March 23, 2016

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.


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