Related Experiment Video
Updated: Mar 25, 2026
Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
Published on: July 30, 2020
MLN-8237: A dual inhibitor of aurora A and B in soft tissue sarcomas
Jayasree S Nair1, Gary K Schwartz1
1Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Abstract:
Aurora kinases have become an attractive target in cancer therapy due to their deregulated expression in human tumors. Liposarcoma, a type of soft tissue sarcoma in adults, account for approximately 20% of all adult soft tissue sarcomas. There are no effective chemotherapies for majority of these tumors. Efforts made to define the molecular basis of liposarcomas lead to the finding that besides the amplifications of CDK4 and MDM2, Aurora Kinase A, also was shown to be overexpressed. Based on these as well as mathematic modeling, we have carried out a successful preclinical study using CDK4 and IGF1R inhibitors in liposarcoma. MLN8237 has been shown to be a potent and selective inhibitor of Aurora A. MLN-8237, as per our results, induces a differential inhibition of Aurora A and B in a dose dependent manner. At a low nanomolar dose, cellular effects such as induction of phospho-Histone H3 (Ser10) mimicked as that of the inhibition of Aurora kinase A followed by apoptosis. However, micromolar dose of MLN-8237 induced polyploidy, a hallmark effect of Aurora B inhibition. The dose dependent selectivity of inhibition was further confirmed by using siRNA specific inhibition of Aurora A and B. This was further tested by time lapse microscopy of GFP-H2B labelled cells treated with MLN-8237. LS141 xenograft model at a dose of 30 mg/kg also showed efficient growth suppression by selective inhibition of Aurora Kinase A. Based on our data, a dose that can target only Aurora A will be more beneficial in tumor suppression.
Insights
Targeting Aurora Kinase A with MLN8237 shows promise for liposarcoma treatment. Selective inhibition at low doses induces apoptosis, offering a potential new therapy for this challenging cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Aurora kinases are frequently overexpressed in human tumors, making them attractive targets for cancer therapy.
- Liposarcoma, a prevalent soft tissue sarcoma, often lacks effective chemotherapy options.
- Overexpression of Aurora Kinase A, alongside CDK4 and MDM2 amplifications, is observed in liposarcoma.
Purpose of the Study:
- To investigate the therapeutic potential of MLN8237, a selective Aurora Kinase A inhibitor, in liposarcoma.
- To determine the dose-dependent effects of MLN8237 on Aurora Kinase A and B inhibition.
- To evaluate the efficacy of MLN8237 in preclinical liposarcoma models.
Main Methods:
- Utilized MLN8237, a potent and selective inhibitor of Aurora A.
- Assessed dose-dependent inhibition of Aurora A and B using cellular assays and siRNA.
- Employed time-lapse microscopy of GFP-H2B labeled cells to observe cellular effects.
- Evaluated tumor growth suppression in a LS141 xenograft model.
Main Results:
- MLN8237 demonstrated differential inhibition of Aurora A and B in a dose-dependent manner.
- Low nanomolar doses of MLN8237 induced apoptosis via Aurora Kinase A inhibition.
- Micromolar doses of MLN8237 resulted in polyploidy, characteristic of Aurora B inhibition.
- MLN8237 (30 mg/kg) significantly suppressed tumor growth in the LS141 xenograft model.
Conclusions:
- Selective inhibition of Aurora Kinase A by MLN8237 is a promising strategy for liposarcoma treatment.
- Dose optimization is crucial to leverage Aurora Kinase A's apoptotic effects while avoiding Aurora B-mediated polyploidy.
- Targeting Aurora Kinase A offers a potential therapeutic avenue for liposarcoma where conventional therapies are limited.
More Related Videos
04:36Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors
Published on: October 17, 2025
06:00Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
Published on: May 14, 2016
Related Concept Videos
02:34Inhibition of Cdk Activity
02:34Inhibition of CDK Activity
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:57Targeted Cancer Therapies
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes