title: Genomic imbalance of HMMR/RHAMM regulates 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.
authors: Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Pooja
authors: P
authors: Mohan
authors: Joan
authors: J
authors: Castellsague
authors: Jihong
authors: J
authors: Jiang
authors: Kristi
authors: K
authors: Allen
authors: Helen
authors: H
authors: Chen
authors: Oksana
authors: O
authors: Nemirovsky
authors: Melanie
authors: M
authors: Spyra
authors: Kaiji
authors: K
authors: Hu
authors: Lan
authors: L
authors: Kluwe
authors: Miguel Angel
authors: MA
authors: Pujana
authors: Alberto
authors: A
authors: Villanueva
authors: Victor F
authors: VF
authors: Mautner
authors: Jonathan J
authors: JJ
authors: Keats
authors: Sandra E
authors: SE
authors: Dunn
authors: Conxi
authors: C
authors: Lazaro
authors: Christopher A
authors: CA
authors: Maxwell
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines; D018797:Cell Cycle Proteins; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; C550258:MLN 8237; C122167:TPX2 protein, human; C098946:hyaluronan-mediated motility receptor; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; C576917:AURKA protein, human; C576918:Aurka protein, mouse