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

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.

The Aurora-A inhibitor MLN8237 affects multiple mitotic processes and induces dose-dependent mitotic abnormalities and aneuploidy

“…The highly aneuploid progeny generated in our assays at 50 nM (and, to a higher extent, 250 nM) MLN8237 originates cells impaired in further cell division, hence unviable in the long term. The mechanisms underlying the cytostatic effects of Aurora-A inactivation are controversial: a dose- and time-dependent induction of apoptosis was described in different cell lines treated with MLN8237 [18, 19, 38, 39], while in other cases the MLN8237-induced cytostatic effect is attributed to senescence [40] consistent with results described in Aurora-A-null MEFs [33], or to induction of differentiation pathways [41]. These observations suggest that both the treatment parameters and the cellular background contribute to determine the long-term outcome of MLN8237-treated cultures.…”

A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells

“…MLN8237, under investigation in multiple phase I and II studies, was active in resistant CML and significantly increased the efficacy of nilotinib treatment (35). Moreover, it reduced the formation of spheroids, attenuated the self-renewal of spheroid forming cells, and promoted cell differentiation (36). Notably, the Aurora inhibitor MK0457 and histone deacetylase inhibitor vorinostat combination was highly active against primary CD34 + CML cells and Ba/F3 cells with BCR-ABL mutations, such as T315I, E255K, and M351T (37).…”

Carcinoma Cell Hyaluronan as a “Portable” Cancerized Prometastatic Microenvironment

“…Several clinical studies also suggest a role for RHAMM in drug resistance that may determine patient outcome. Thus, the therapeutic sensitivity of peripheral nerve sheath tumors to therapy targeting AURKA depends in part upon RHAMM expression [39], and multidrug resistance of some human leukemia cell lines is mediated by RHAMM [48]. These and other studies suggest RHAMM hyperexpression in aggressive tumor cell subsets has promise as a biomarker for assessing patient risk.…”