Genomic imbalance ofHMMR/RHAMMregulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition

Pooja Mohan,Kristi Allen,Sandra E Dunn,Oksana Nemirovsky,Victor F Mautner,Joan Castellsague,Christopher A Maxwell,Lan Kluwe,Jihong Jiang,Conxi Lazaro,Helen Chen,Melanie Spyra,Miguel Angel Pujana,Alberto Villanueva,Jonathan J Keats,Kaiji Hu

doi:10.18632/oncotarget.793

Abstract

Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM.

Highlights

Neurofibromatosis type I is an autosomal dominant, tumour predisposition syndrome [1]
In common with their report, we identified genomic amplification of Aurora kinase A (AURKA) in Malignant peripheral nerve sheath tumours (MPNST) cell-lines (Fig S2B) and found that robust inhibition of growth in vitro followed the silencing of AURKA or the treatment of cells with aurora kinase inhibitor (AKI), which stabilized the growth of two primary, human MPNST when grown as xenotransplants in animal models
By studying the responses of primary human MPNSTs grown in vivo, our animal models contain non-neoplastic cells from the human tumour environment, which are critical for tumourigenicity [24]

Summary

Introduction

Neurofibromatosis type I is an autosomal dominant, tumour predisposition syndrome [1]. Patel and colleagues identified Aurora kinase A (AURKA) as a candidate target for MPNST therapy by first modeling the disease in an animal model, identifying frequent amplification of AURKA in human tumours, and treating MPNST cell-lines grown in vitro and as xenotransplants in vivo with an AURKA specific inhibitor, termed MLN8237 [5]. Treatment of an MPNST cell-line with MLN8237 stabilized the cell-line’s growth in vivo and induced endoreduplication and senescence in vitro [5]. Optimal application of these emerging therapies will require a better understanding and prediction of MPNST susceptibilities and tumour cell responses

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