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.
Highlights
Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product that is approved for treatment of patients with advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer [1]
To identify the key factors needed for the DNA damage response (DDR) to trabectedin and lurbinectedin, we first determined the activity of ataxia-telangiectasia mutated (ATM)
Coherent with the results for ATM, both trabectedin and www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget lurbinectedin treatments lead to the activation of Chk2 through phosphorylation on Thr68 (Figure 2)
Summary
Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product that is approved for treatment of patients with advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer [1]. Lurbinectedin is structurally similar to trabectedin except for a tetrahydroisoquinoline present in trabectedin that is replaced by a tetrahydro β-carboline in lurbinectedin [3] This structural variation is accompanied by important modifications of the pharmacokinetic and pharmacodynamic properties in cancer patients the preclinical activities of lurbinectedin remain close to those observed for trabectedin [4,5]. Due to their original mechanism of action, trabectedin and lurbinectedin are associated with an unusual pattern of sensitivity in DNA repair-deficient cells [1]. Inhibition of the cell cycle checkpoints that are activated in response to trabectedin might prove useful in order to increase drug efficacy [16,17]
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