Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy.

Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.

Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.

Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.

In vitro evaluation of Neosetophomone B inducing apoptosis in cutaneous T cell lymphoma by targeting the FOXM1 signaling pathway.

BACKGROUND: Cutaneous T cell lymphoma (CTCL) is a T cell-derived non-Hodgkin lymphoma primarily affecting the skin, with treatment posing a significant challenge and low survival rates. OBJECTIVE: In this study, we investigated the anti-cancer potential of Neosetophomone B (NSP-B), a fungal-derived secondary metabolite, on CTCL cell lines H9 and HH. METHODS: Cell viability was measured using Cell counting Kit-8 (CCK8) assays. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Applied Biosystems' high-resolution Human Transcriptome Array 2.0 was used to examine gene expression. RESULTS: NSP-B induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases. We observed downregulated expression of BUB1B, Aurora Kinases A and B, cyclin-dependent kinases (CDKs) 4 and 6, and polo-like kinase 1 (PLK1) in NSP-B treated cells, which was further corroborated by Western blot analysis. Notably, higher expression levels of these genes showed reduced overall and progression-free survival in the CTCL patient cohort. FOXM1 and BUB1B expression exhibited a dose-dependent reduction in NSP-B-treated CTCL cells.FOXM1 silencing decreased cell viability and increased apoptosis via BUB1B downregulation. Moreover, NSP-B suppressed FOXM1-regulated genes, such as Aurora Kinases A and B, CDKs 4 and 6, and PLK1. The combined treatment of Bortezomib and NSP-B showed greater efficacy in reducing CTCL cell viability and promoting apoptosis compared to either treatment alone. CONCLUSION: Our findings suggest that targeting the FOXM1 pathway may provide a promising therapeutic strategy for CTCL management, with NSP-B offering significant potential as a novel treatment option.

Combined Aurora Kinase A and CHK1 Inhibition Enhances Radiosensitivity of Triple-Negative Breast Cancer Through Induction of Apoptosis and Mitotic Catastrophe Associated With Excessive DNA Damage.

PURPOSE: There is an urgent need for biomarkers and new actionable targets to improve radiosensitivity of triple-negative breast cancer (TNBC) tumors. We characterized the radiosensitizing effects and underlying mechanisms of combined Aurora kinase A (AURKA) and CHK1 inhibition in TNBC. METHODS AND MATERIALS: Different TNBC cell lines were treated with AURKA inhibitor (AURKAi, MLN8237) and CHK1 inhibitor (CHK1i, MK8776). Cell responses to irradiation (IR) were then evaluated. Cell apoptosis, DNA damage, cell cycle distribution, and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and Phosphoinositide 3-Kinase (PI3K) pathways were evaluated in vitro. Transcriptomic analysis was performed to facilitate the identification of potential biomarkers. Xenograft and immunohistochemistry were carried out to investigate the radiosensitizing effects of dual inhibition in vivo. Finally, the prognostic effect of CHEK1/AURKA in TNBC samples in the The Cancer Genome Atlas (TCGA) database and our center were analyzed. RESULTS: AURKAi (MLN8237) induced overexpression of phospho-CHK1 in TNBC cells. The addition of MK8776 (CHK1i) to MLN8237 greatly reduced cell viability and increased radiosensitivity compared with either the control or MLN8237 alone in vitro. Mechanistically, dual inhibition resulted in inducing excessive DNA damage by prompting G2/M transition to cells with defective spindles, leading to mitotic catastrophe and induction of apoptosis after IR. We also observed that dual inhibition suppressed the phosphorylation of ERK, while activation of ERK with its agonist or overexpression of active ERK1/2 allele could attenuate the apoptosis induced by dual inhibition with IR. Additionally, dual inhibition of AURKA and CHK1 synergistically enhanced radiosensitivity in MDA-MB-231 xenografts. Moreover, we detected that both CHEK1 and AURKA were overexpressed in patients with TNBC and negatively correlated with patient survival. CONCLUSIONS: Our findings suggested that AURKAi in combination with CHK1i enhanced TNBC radiosensitivity in preclinical models, potentially providing a novel strategy of precision treatment for patients with TNBC.

The heterogeneous transition state of resistance to RET kinase inhibitors converges on ERK1/2-driven Aurora A/B kinases.

AIM: While most patients with RET-altered cancer responded to the RET protein tyrosine kinase inhibitors (TKIs) pralsetinib (BLU667) and selpercatinib (LOXO292), few achieved a complete response. Heterogeneity in residual tumors makes it difficult to target their diverse genetic alterations individually. The aim of this study is to characterize the cancer cells that persist under continuous RET TKI treatment and identify the shared vulnerability of these cells. METHODS: We analyzed residual RET-altered cancer cells under prolonged RET TKI treatment by whole exome sequencing (WES), RNA-seq analysis, and drug-sensitivity screening. These were followed by tumor xenograft experiments of mono- and combinational drug treatments. RESULTS: BLU667- and LOXO292-tolerated persisters were cellularly heterogeneous, contained slowly proliferating cells, regained low levels of active ERK1/2, and displayed plasticity in growth rate, which we designated as in the transition state of resistance (TSR). TSR cells were genetically heterogeneous. Aurora A/B kinases were among the most significantly upregulated genes and that the MAPK pathway activity had significantly higher transcript footprints. MEK1/2 and Aurora kinase inhibitors were the most effective drugs when combined with a RET kinase inhibitor. In a TSR tumor model, combination of BLU667 with an Aurora kinase or a MEK1/2 kinase inhibitor caused TSR tumor regression. CONCLUSION: Our experiments reveal that the heterogeneous TSR cancer cells under continuous RET TKI treatment converge on the targetable ERK1/2-driven Aurora A/B kinases. The discovery of the targetable convergent point in the genetically heterogeneous TSR points to an effective combination therapy approach to eliminate the residual tumors.

The promotion action of AURKA on post-ischemic angiogenesis in diabetes-related limb ischemia.

BACKGROUND: Diabetes-related limb ischemia is a challenge for lower extremity amputation. Aurora Kinase A (AURKA) is an essential serine/threonine kinase for mitosis, while its role in limb ischemia remains unclear. METHOD: Human microvascular endothelial cells (HMEC-1) were cultured in high glucose (HG, 25 mmol/L D-glucose) and no additional growth factors (ND) medium to mimic diabetes and low growth factors deprivation as in vitro model. Diabetic C57BL/6 mice were induced by streptozotocin (STZ) administration. After seven days, ischemia was surgically performed by left unilateral femoral artery ligation on diabetic mice. The vector of adenovirus was utilized to overexpress AURKA in vitro and in vivo. RESULTS: In our study, HG and ND-mediated downregulation of AURKA impaired the cell cycle progression, proliferation, migration, and tube formation ability of HMEC-1, which were rescued by overexpressed AURKA. Increased expression of vascular endothelial growth factor A (VEGFA) induced by overexpressed AURKA were likely regulatory molecules that coordinate these events. Mice with AURKA overexpression exhibited improved angiogenesis in response to VEGF in Matrigel plug assay, with increased capillary density and hemoglobin content. In diabetic limb ischemia mice, AURKA overexpression rescued blood perfusion and motor deficits, accompanied by the recovery of gastrocnemius muscles observed by H&E staining and positive Desmin staining. Moreover, AURKA overexpression rescued diabetes-related impairment of angiogenesis, arteriogenesis, and functional recovery in the ischemic limb. Signal pathway results revealed that VEGFR2/PI3K/AKT pathway might be involved in AURKA triggered angiogenesis procedure. In addition, AURKA overexpression impeded oxidative stress and subsequent following lipid peroxidation both in vitro and in vivo, indicating another protective mechanism of AURKA function in diabetic limb ischemia. The changes in lipid peroxidation biomarkers (lipid ROS, GPX4, SLC7A11, ALOX5, and ASLC4) in in vitro and in vivo were suggestive of the possible involvement of ferroptosis and interaction between AUKRA and ferroptosis in diabetic limb ischemia, which need further investigation. CONCLUSIONS: These results implicated a potent role of AURKA in diabetes-related impairment of ischemia-mediated angiogenesis and implied a potential therapeutic target for ischemic diseases of diabetes.

Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer: The Phase 2 TBCRC041 Randomized Clinical Trial.

Importance: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown. Objective: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022. Interventions: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). Main Outcomes and Measures: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. Results: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). Conclusions and Relevance: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT02860000.

Murine Central Nervous System and Bone Marrow Distribution of the Aurora A Kinase Inhibitor Alisertib: Pharmacokinetics and Exposure at the Sites of Efficacy and Toxicity.

Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma, and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events.Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted. SIGNIFICANCE STATEMENT: The CNS penetration of alisertib is limited with uniform distribution in various regions of the brain, and P-gp efflux is an important mechanism limiting that CNS distribution. Alisertib rapidly distributes into the bone marrow, a site of toxicity, with a greater exposure than in the CNS, a possible site of efficacy. These results suggest a need to design localized delivery strategies to improve the CNS exposure of alisertib and limit systemic toxicities in the treatment of brain tumors.

CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial-mesenchymal transition, G2/M phase transition, and PANoptosis.

BACKGROUND: Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. METHODS: By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. RESULTS: Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. CONCLUSIONS: CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.

Disease Modeling on Tumor Organoids Implicates AURKA as a Therapeutic Target in Liver Metastatic Colorectal Cancer.

BACKGROUND & AIMS: Patient-derived tumor organoids recapitulate the characteristics of colorectal cancer (CRC) and provide an ideal platform for preclinical evaluation of personalized treatment options. We aimed to model the acquisition of chemotolerance during first-line combination chemotherapy in metastatic CRC organoids. METHODS: We performed next-generation sequencing to study the evolution of KRAS wild-type CRC organoids during adaptation to irinotecan-based chemotherapy combined with epidermal growth factor receptor (EGFR) inhibition. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 protein (Cas9)-editing showed the specific effect of KRASG12D acquisition in drug-tolerant organoids. Compound treatment strategies involving Aurora kinase A (AURKA) inhibition were assessed for their capability to induce apoptosis in a drug-persister background. Immunohistochemical detection of AURKA was performed on a patient-matched cohort of primary tumors and derived liver metastases. RESULTS: Adaptation to combination chemotherapy was accompanied by transcriptomic rather than gene mutational alterations in CRC organoids. Drug-tolerant cells evaded apoptosis and up-regulated MYC (c-myelocytomatosis oncogene product)/E2F1 (E2 family transcription factor 1) and/or interferon-α-related gene expression. Introduction of KRASG12D further increased the resilience of drug-persister CRC organoids against combination therapy. AURKA inhibition restored an apoptotic response in drug-tolerant KRAS-wild-type organoids. In dual epidermal growth factor receptor (EGFR)- pathway blockade-primed CRC organoids expressing KRASG12D, AURKA inhibition augmented apoptosis in cases that had acquired increased c-MYC protein levels during chemotolerance development. In patient-matched CRC cohorts, AURKA expression was increased in primary tumors and derived liver metastases. CONCLUSIONS: Our study emphasizes the potential of patient-derived CRC organoids in modeling chemotherapy tolerance ex vivo. The applied therapeutic strategy of dual EGFR pathway blockade in combination with AURKA inhibition may prove effective for second-line treatment of chemotolerant CRC liver metastases with acquired KRAS mutation and increased AURKA/c-MYC expression.

CCNB1 and AURKA are critical genes for prostate cancer progression and castration-resistant prostate cancer resistant to vinblastine.

Background: Prostate cancer (PCa) is a common malignancy occurring in men. As both an endocrine and gonadal organ, prostate is closely correlated with androgen. So, androgen deprivation therapy (ADT) is effective for treating PCa. However, patients will develop castration-resistant prostate cancer (CRPC) stage after ADT. Many other treatments for CRPC exist, including chemotherapy. Vinblastine, a chemotherapeutic drug, is used to treat CRPC. However, patients will develop resistance to vinblastine. Genetic alterations have been speculated to play a critical role in CRPC resistance to vinblastine; however, its mechanism remains unclear. Methods: Various databases, such as Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA), were used to collect the RNA-sequence data of PCa and CRPC patients and vinblastine-resistant PCa cells. Using online tools, Metascape and TIMER, the pathways and immune infiltration associated with vinblastine resistance-related genes in PCa were analyzed. The function of these genes was verified in clinical samples and CRPC cells. Results: Using GSE81277 dataset, we collected the RNA-sequence data of vinblastine sensitive and resistant LNCaP cells and found nine genes (CDC20, LRRFIP1, CCNB1, GPSM2, AURKA, EBLN2, CCDC150, CENPA and TROAP) that correlated with vinblastine resistance. Furthermore, CCNB1, GPSM2 and AURKA were differently expressed between normal prostate and PCa tissues, even influencing PCa progression. The GSE35988 dataset revealed that CCNB1 and AURKA were upregulated in PCa and CRPC samples. Various genes were also found to affect the survival status of PCa patients based on TCGA. These genes were also related to immune cell infiltration. Finally, we verified the function of CCNB1 and AURKA and observed that they were upregulated in PCa and CRPC clinical samples and increased the sensitivity of CRPC cells to vinblastine. Conclusion: CCNB1 and AURKA are central to CRPC resistance to vinblastine and affect PCa progression.

Efficacy and Safety of Weekly Paclitaxel With or Without Oral Alisertib in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial.

Importance: Elevated expression of AURKA adversely affects prognosis in estrogen receptor (ER)-positive and ERBB2 (formerly HER2)-negative and triple-negative breast cancer and is associated with resistance to taxanes. Objective: To compare paclitaxel alone vs paclitaxel plus alisertib in patients with ER-positive and ERBB2-negative or triple-negative metastatic breast cancer (MBC). Design, Setting, and Participants: In this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m2 on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m2 on days 1, 8, and 15 plus oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Stratification was by prior neo or adjuvant taxane and by line of metastatic therapy. Eligible patients were those who had undergone endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, more than 12 months treatment-free interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bone-disease. Data were analyzed from March 2019 through May 2019. Main Outcomes and Measures: The main outcome was progression-free survival (PFS) with secondary end points of overall survival (OS), overall response rate, clinical benefit rate, safety, and analysis of archival breast cancer tissues for molecular markers associated with benefit from alisertib. Results: A total of 174 patients were randomized, including with 86 randomized to paclitaxel and 88 patients randomized to paclitaxel plus alisertib, and 169 patients received study treatment. The final cohort included 139 patients with a median (interquartile range [IQR]) age of 62 (27-84) years with ER-positive and ERBB2-negative MBC, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TNBC cohort closed with only 35 patients enrolled due to slow accrual and were not included in efficacy analyses. The median (IQR) follow-up was 22 (10.6-25.1) months, and median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) months with paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005). Median (IQR) OS was 26.3 (12.4-37.2) months for patients who received paclitaxel plus alisertib vs 25.1 (11.0-31.4) months for paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). Grade 3 or 4 adverse events occurred in 56 patients (84.8%) receiving paclitaxel plus alisertib vs 34 patients (48.6%) receiving paclitaxel alone. The main grade 3 or 4 adverse events with paclitaxel plus alisertib vs paclitaxel alone were neutropenia (50 patients [59.5%] vs 14 patients [16.4%]), anemia (8 patients [9.5%] vs 1 patient [1.2%]), diarrhea (9 patients [10.7%] vs 0 patients), and stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients). One patient receiving paclitaxel plus alisertib died of sepsis. Conclusions and Relevance: This randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. These data support further evaluation of alisertib in patients with ER-positive, ERBB2-negative MBC. Trial Registration: ClinicalTrials.gov Identifier: NCT02187991.

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

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.