Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors

Abstract

Although imatinib mesylate (IM) has revolutionized the management of gastrointestinal stromal tumors (GISTs), drug resistance remains a challenge. Previous studies have shown that the expression of aurora kinase A (AURKA) predicts recurrence in patients with primary, surgically resected GISTs. The current study aimed to evaluate the significance of AURKA expression as an unfavorable prognostic marker for advanced GISTs, and provide evidence that AURKA could be a potential therapeutic target in GISTs. The prognostic significance of the expression of AURKA, along with other clinicopathological factors, was analyzed in a cohort of 99 IM-treated patients with advanced GISTs. The potential use of an inhibitor of AURKA as a therapeutic agent against GISTs was also tested in GIST cell lines. Among 99 enrolled patients, poor performance status, large tumor size, drug response, and AURKA overexpression were independent prognostic factors for poor progression-free survival (PFS). For overall survival (OS), only large tumor size and AURKA overexpression were identified as independent unfavorable factors. In an in vitro study, MLN8237, an AURKA inhibitor, inhibited growth of both IM-sensitive and IM-resistant GIST cells in a concentration-dependent manner, and exhibited synergistic cytotoxicity with IM in GIST cells. The inhibitory effect of MLN8237 in GIST cells could be attributed to the induction of G2/M arrest, apoptosis, and senescence. Our study shows that AURKA expression independently predicted poor PFS and OS in patients with advanced GISTs who were treated with IM. An AURKA inhibitor may have potential as a therapeutic agent for both IM-sensitive and IM-resistant GISTs.

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

“…In the present study, GSK461364 treatment significantly increased SA-β-gal activity and enhanced the expression of DcR2 and IL-1α in OS cell lines. In addition, similar findings were revealed in our previous study of AURKA inhibitor MLN8237 in the treatment of GIST cell line (39). Our studies indicated that cellular senescence is a crucial phenotype of PLK1, or in treatment of other cell cycle inhibitors and that senescence-associated markers may be valuable biomarkers for therapy with these compounds.…”

“…Moreover, by reanalyzing a dataset of GIST, our group identified aurora kinase A (AURKA), along with other cell cycle and mitosis genes, as a prognostic factor for recurrence. In addition, AURKA is a potential treatment target (38,39). Therefore, cell cycle regulation genes are a crucial group of potential biomarkers or targets in sarcoma.…”

PDGFRβ and oncogenic, mutant PDGFRα D842V promote disassembly of primary cilia by a PLCγ and AURKA dependent mechanism

“…Notably, chimeric mice lacking endogenous PDGFRβ display renal cysts and glomerulosclerosis (Klinghoffer et al, 2001), phenotypes associated with defective intracellular Ca 2+ signaling (Kuo et al, 2014) and ciliopathies (Hildebrandt et al, 2011). Because PDGFRα D842V and AURKA expression is linked to GIST (Corless et al, 2011;Yeh et al, 2014), and precursors of GIST cells are ciliated (Castiella et al, 2013), it will be interesting to study whether GIST cells display ciliary defects that are caused by elevated PLCγ and AURKA activity.…”

Prognostic value of Aurora kinase A (AURKA) expression among solid tumor patients: a systematic review and meta-analysis

“…Four studies analyzing AURKA mRNA expression used real-time reverse transcription PCR (RT-PCR) (20,34,35,45); one study analyzing AURKA gene amplification by fluorescence in situ hybridization (FISH) (54); the other one used immunohistochemical (IHC) staining and RT-PCR (47); and the remaining 33 studies applied a immunohistochemistry detection method (9,18,19,21-23,27-33, 36-44,46,48-53,55-58). Eight studies were conducted in patients from European countries (19,21,28,32,36,40,55,57), four in patients from USA (18,20,37,45), three in Oceania countries (33,46,49), one in South America (50), and twenty-three in Asian countries (9,22,23,27,(29)(30)(31)34,35,38,39,(41)(42)(43)(44)47,48,(51)(52)(53)(54)56,58). One or more oncologic outcome parameters were analyzed on multivariate analysis in 33 studies <...>…”

“…One or more oncologic outcome parameters were analyzed on multivariate analysis in 33 studies (9,(18)(19)(20)(21)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)58). A significant association between high AURKA expression and the poor prognosis of patients was reported in 71.4% of studies on OS (9,18,31,32,(34)(35)(36)(37)39,(42)(43)(44)(45)48,(50)(51)(52)(53)…”