Abstract
Abstract Introduction: Trabectedin (T) is a marine-derived anticancer drug with a peculiar mechanism of action, ascribed to a covalent modification of DNA by guanine-specific alkylation at the N2 position in the minor groove that induces DNA damage, affects transcription regulation and triggers cell differentiation and death. Trabectedin has been approved in the EU for the second line treatment of soft tissue sarcomas and ovarian carcinomas. In order to investigate the mechanisms of resistance to trabectedin, that generally occurs after prolonged treatment with the drug, two different trabectedin-resistant cell lines such as myxoid liposarcoma 402-91 and ovarian carcinoma A2780 were developed and characterized. Material and Methods: Resistant cell lines (402-91/T and A2780/T) were obtained by stepwise increase in drug concentration using a short exposure (1 hr) applied at 10-20 day intervals. Drug sensitivity was measured by colony assay, DNA content and cell cycle were evaluated by flow cytometric analysis and XPG expression by Western Blotting. Results: 402-91/T and A2780/T cell lines were 16 and 6 fold resistant to trabectedin as compared to parental cells respectively. Resistant cell lines maintained the same DNA content compared with the parental cells, while showed different cell cycle perturbations induced by trabectedin treatment; in fact the characteristic G2/M block was found only in sensitive cell lines. Both 402-91/T and A2780/T cell lines did not express XPG, a protein involved in NER pathway, and were found hypersensitive to UV light. This finding is in keeping with previous observations that NER deficiency is associated to a decreased sensitivity to trabectedin. Being NER activity crucial for the repair of platinum DNA adducts, we tested cisplatin cytotoxicity in 402-91/T and A2780/T cell lines and they were 2.5 and 11 fold more sensitive than the parental cell lines. The collateral sensitivity to cisplatin of trabectedin resistant cell lines is likely related to the important function of NER in the repair of the bulky adducts produced by the drug. Conclusion: The finding that resistance to trabectedin is associated to the loss of NER function, with consequent increased sensitivity to cisplatin, provides the rational to test the sequential combination of trabectedin and platinum complexes in the clinic. This strategy is currently under evaluation in ovarian cancer patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C93. Citation Format: Maurizio D'Incalci, Benedetta Colmegna, Sarah Uboldi, Roberta Frapolli, Simonetta Andrea Licandro, Eugenio Erba, Carlos M. Galmarini, Nadia Badri. Collateral sensitivity to cisplatin of trabectedin-resistant cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C93.
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