Establishment and characterisation of a new patient-derived model of myxoid liposarcoma with acquired resistance to trabectedin

Ezia Bello,Paolo Giovanni Casali,Alessandro Gronchi,Sergio Marchini,Roberta Frapolli,Raffaella Gatta,Maurizio D’Incalci,Silvana Pilotti,Ilaria Craparotta,Silvia Brich,Cristina Matteo,Laura Carrassa,Laura Mannarino,Roberta Sanfilippo,Sara Ballabio

doi:10.1038/s41416-019-0550-2

Abstract

BackgroundMyxoid liposarcoma is a histological subtype of liposarcoma particularly sensitive to trabectedin. In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. No other effective therapies are available for trabectedin-resistant patients.MethodsThrough repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin.ResultsAt basal level, the morphology of the resistant and sensitive models did not differ, in keeping with the finding that the transcriptional profiles of the resistant and sensitive tumours were very similar. After trabectedin treatment adipogenesis was induced in the parental xenograft but not in the resistant one, as assessed by pathological and molecular analysis. A defective transcription-coupled-nucleotide excision repair in the resistant tumour due to mutation of the UVSSA gene may be implicated in the mechanism of resistance.ConclusionsThis is the first in vivo model of myxoid liposarcoma with acquired resistance to trabectedin. Although further studies are necessary to characterise the resistance mechanisms, this is a useful tool for studying new therapeutic strategies to overcome trabectedin resistance in patients.

Highlights

Myxoid liposarcoma is a histological subtype of liposarcoma sensitive to trabectedin
To further characterise the pharmacological behaviour of the ML017/ET model, we investigated the sensitivity to doxorubicin and lurbinectedin
The present study reports the characterisation of a Myxoid liposarcoma (MLS) patientderived xenograft with acquired resistance to trabectedin

Summary

Introduction

Myxoid liposarcoma is a histological subtype of liposarcoma sensitive to trabectedin In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. Myxoid liposarcoma (MLS) is the second most common liposarcoma (35–40%) It arises mainly in the deep soft tissue of the extremities at a median age of incidence of 45 years. It is characterised by a myxoid stroma with a distinctive plexiform vascular network and low cellularity composed of round/oval non-lipogenic cells, lipoblasts and mature adipocytes. MLS has an indolent clinical progression, but a subset of patients shows a more aggressive behaviour This high-grade subtype has high cellularity composed mainly of non-lipogenic round cells and few myxoid stroma. High-grade MLS has an unusual pattern of dissemination: main sites of metastasis are serous membranes (peritoneum, pleura, and pericardium), abdominal cavity and distant soft tissues, and bones.[1]

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