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Br J Cancer. 2015 Dec 22;113(12):1687-93. doi: 10.1038/bjc.2015.407. Epub 2015 Dec 3.

Increased sensitivity to platinum drugs of cancer cells with acquired resistance to trabectedin.

Author information

1
Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy.
2
Department of Research and Development (R&D), PharmaMar S.A., Colmenar Viejo, Madrid 28770, Spain.
3
Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.

Abstract

BACKGROUND:

In order to investigate the mechanisms of acquired resistance to trabectedin, trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo.

METHODS:

Resistant cell lines were obtained by repeated exposures to trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts.

RESULTS:

402-91/T and A2780/T cells were six-fold resistant to trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks.

CONCLUSIONS:

Our finding that resistance to trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to trabectedin.

PMID:
26633559
PMCID:
PMC4701998
DOI:
10.1038/bjc.2015.407
[Indexed for MEDLINE]
Free PMC Article

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