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Modification of RHAMM and TPX2 optimizes Aurora kinase A (AURKA) inhibition in malignant peripheral nerve sheath tumours

University of British Columbia

Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatments as they often resist chemotherapies and have high rates of disease recurrence. Published analysis of copy number variation identified hemizygous loss of Hyaluronan Mediated Motility Receptor (HMMR, encodes RHAMM) in half of the examined high-grade MPNST, but not in benign neurofibromas or low grade tumours. RHAMM is a molecular brake for the mitotic kinase Aurora A (AURKA), so this loss of HMMR in high-grade MPNST may cause tumours to rely on AURKA activity and sensitizes them to aurora kinase inhibitors (AKI). Three MPNST cell-lines were profiled for the expression and activity of AURKA, as well as their responses to three AKI. The sensitivity of cell-lines with amplification of AURKA was reliant upon kinase activity, which correlated with the expression of the regulatory gene products TPX2 and RHAMM. Silencing of RHAMM, but not TPX2, increased AURKA activity and sensitized MPNST cells to AKI. All three AKIs reduced kinase activity in a dose-dependent manner, and AKI treatment induced cellular responses such as apoptosis, endoreduplication and cellular senescence. Additionally, two primary human MPNSTs grown in vivo as xenotransplants were treated with the AURKA-specific inhibitor MLN8237. Treatment resulted in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulated in stabilized disease. The MPNST cell-line S462 has a population of tumorigenic stem-like cells that can be grown in sphere culture. AURKA activity was critical to the propagation and self-renewal of sphere-enriched MPNST stem-like cells. AKI treatment significantly reduced the formation of spheroids, attenuated the self-renewal of spheroid forming cells, and promoted their differentiation. Silencing of TPX2 decreased AURKA activity, while silencing of RHAMM was 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 RHAMM and TPX2.

Text

2013-04-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44345

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/