Pan Aurora Kinase Inhibitor: A Promising Targeted-Therapy in Dedifferentiated Liposarcomas With Differential Efficiency Depending on Sarcoma Molecular Profile.

Jean Camille Mattei,Doriane Barets,Mathieu Chocry,Philippe Morando,Sébastien Salas,Nicolas Macagno,Corinne Bouvier-Labit,Carine Jiguet-Jiglaire,Florence Duffaud,Frédéric Chibon,Richard Alexandre Rochwerger,Sylviane Olschwang

doi:10.3390/cancers12030583

Abstract

Soft tissue sarcoma (STS) are rare and aggressive tumours. Their classification includes numerous histological subtypes of frequent poor prognosis. Liposarcomas (LPS) are the most frequent type among them, and the aggressiveness and deep localization of dedifferentiated LPS are linked to high levels of recurrence. Current treatments available today lead to five-year overall survival has remained stuck around 60–70% for the past three decades. Here, we highlight a correlation between Aurora kinasa A (AURKA) and AURKB mRNA overexpression and a low metastasis-free survival. AURKA and AURKB expression analysis at genomic and protein level on a 9-STS cell lines panel highlighted STS heterogeneity, especially in LPS subtype. AURKA and AURKB inhibition by RNAi and drug targeting with AMG 900, a pan Aurora Kinase inhibitor, in four LPS cell lines reduces cell survival and clonogenic proliferation, inducing apoptosis and polyploidy. When combined with doxorubicin, the standard treatment in STS, aurora kinases inhibitor can be considered as an enhancer of standard treatment or as an independent drug. Kinome analysis suggested its effect was linked to the inhibition of the MAP-kinase pathway, with differential drug resistance profiles depending on molecular characteristics of the tumor. Aurora Kinase inhibition by AMG 900 could be a promising therapy in STS.

Highlights

IntroductionThey are rare tumours of a 4–5/10000/year incidence in Europe [2] with high aggressiveness, accounting for 5200 deaths in 2015 in the US [3]
Soft tissue sarcomas (STS) constitute a heterogeneous group of connective tissue malignant tumours involving limbs in 50% of cases, retroperitoneum/trunk in 40% and head/neck soft tissue in10% [1]
We report in this work the effect of Aurora kinasa A (AURKA) and AURKB inhibition by AMG 900, doxorubicin or both in different sarcoma cell lines, focusing on 4 dedifferentiated liposarcomas

Summary

Introduction

They are rare tumours of a 4–5/10000/year incidence in Europe [2] with high aggressiveness, accounting for 5200 deaths in 2015 in the US [3]. Molecular aspects have to be depicted to understand biological mechanisms and their heterogeneity (especially their complex genomic profiles) precludes the development of numerous, potentially effective antitumor agents. Doxorubicin, an intercalating agent blocking nucleic acid synthesis, has been used as the main drug in metastatic STS since the 1980s [5]. Its high haematological toxicity often contraindicates use in elderly population. The five-years overall survival is low, around 60–70% in localized pathology and it is of utmost importance to identify alternative more efficient drugs with less severe adverse effects to improve the prognosis of STS, notably in the elderly

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