Mohan Pooja, Castellsague Joan, Jiang Jihong, Allen Kristi, Chen Helen, Nemirovsky Oksana, Spyra Melanie, Hu Kaiji, Kluwe Lan, Pujana Miguel Angel, Villanueva Alberto, Mautner Victor F, Keats Jonathan J, Dunn Sandra E, Lazaro Conxi, Maxwell Christopher A
Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Oncotarget. 2013 Jan;4(1):80-93. doi: 10.18632/oncotarget.793.
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.
恶性外周神经鞘瘤（MPNST）是一种罕见的遗传性癌症，与I型神经纤维瘤病相关。MPNST缺乏有效的治疗方案，因为它们常常对化疗产生耐药性，且疾病复发率很高。极光激酶A（AURKA）是癌症领域一个新出现的靶点，一种名为MLN8237的极光激酶抑制剂（AKI）在体外和体内对MPNST细胞系均显示出疗效。在此，我们针对两种在体内作为异种移植生长的原发性人MPNST测试了MLN8237，发现治疗导致肿瘤细胞退出细胞周期并进行核内复制，最终使疾病稳定。由于对决定肿瘤易感性的因素了解不足，靶向治疗在临床上常常失败，因此我们转向三种MPNST细胞系，以进一步研究并调节细胞对AKI的反应。我们发现，AURKA扩增的细胞系的敏感性取决于激酶的活性，而激酶活性与调节基因产物TPX2和HMMR/RHAMM的表达相关。沉默HMMR/RHAMM而非TPX2可增强AURKA活性，并使MPNST细胞对AKI敏感。此外，我们发现AURKA活性对于富含球状体的MPNST癌症干细胞样细胞的增殖和自我更新至关重要。AKI治疗显著减少球状体的形成，减弱球状体形成细胞的自我更新，并促进其分化。此外，沉默HMMR/RHAMM足以赋予MPNST细胞形成并维持球状体培养的能力。总体而言，我们的数据表明，AURKA是MPNST的合理治疗靶点，且肿瘤细胞对AKI的反应（包括分化）受HMMR/RHAMM丰度的调节。
