Increased Sensitivity to Platinum Drugs of Cancer Cells with Acquired Resistance to Trabectedin

Overview

Journal Br J Cancer

Specialty Oncology

Date 2015 Dec 4

PMID 26633559

Citations 15

Authors

B Colmegna

S Uboldi

R Frapolli

S A Licandro

N Panini

C M Galmarini

Nadia Badri

V J Spanswick

J P Bingham

Konstantinos Kiakos

E Erba

J A Hartley

M DIncalci

Affiliations

Soon will be listed here.

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.

Citing Articles

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Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment-Progresses in Their Use in Combined Cancer Therapy.

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Results of a Phase II Trial Testing the Resensitization With Trabectedin in Platinum-resistant Ovarian Cancer.

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INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12....

Colombo N, Gadducci A, Sehouli J, Rulli E, Maenpaa J, Sessa C Br J Cancer. 2023; 128(8):1503-1513.

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Trabectedin and lurbinectedin: Mechanisms of action, clinical impact, and future perspectives in uterine and soft tissue sarcoma, ovarian carcinoma, and endometrial carcinoma.

Gadducci A, Cosio S Front Oncol. 2022; 12:914342.

PMID: 36408147 PMC: 9671549. DOI: 10.3389/fonc.2022.914342.

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