The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation

Abstract

The selective Aurora-A kinase inhibitor MLN8237 is in clinical trials for hematologic malignancies, ovarian cancer and other solid tumors. We previously showed that MLN8237 is potently antiproliferative toward standard monolayer cultured glioblastoma cells. We have now investigated the effect of MLN8237 with and without temozolomide or ionizing radiation on the proliferation of glioblastoma tumor stem-like cells (neurospheres) using soft agar colony formation assays and normal human astrocytes by MTT assay. Western blotting was utilized to compare MLN8237 IC50s to cellular Aurora-A and phospho-Thr288-Aurora-A levels. MLN8237 was more potently antiproliferative to neurosphere cells than to standard monolayer glioma cells, and was non-toxic to normal human astrocytes. Western blot analysis revealed that MLN8237 treatment inhibits phospho-Thr288-Aurora–A levels providing proof of drug target-hit in glioblastoma cells. Furthermore, phospho-Thr288-Aurora-A levels partially predicted the antiproliferative efficacy of MLN8237. We also found that Aurora-A inhibition by MLN8237 was synergistic with temozolomide and potentiated the effects of ionizing radiation on colony formation in neurosphere glioblastoma tumor stem-like cells. These results further support the potential of Aurora-A inhibitors as primary chemotherapy agents or biological response modifiers in glioblastoma patients.

Aurora-A Inhibition Offers a Novel Therapy Effective against Intracranial Glioblastoma

“…S1A). Observed alisertib IC 50 concentrations are similar to slightly higher than those required to inhibit colony formation in 2 other GB neurosphere lines (14) and approximately 5 to 10-fold less than those effective against 10 conventional monolayer GB cell lines (15) suggesting greater efficacy against GB neurosphere cells.…”

Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma

“…Cell line data also indicates additive or synergistic effect with temozolomide and ionizing radiation [31]. Although in vivo demonstration of synergy with temozolomide and radiation is at this point missing, this represents a direction that also merits further preclinical investigation.…”

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

“…MLN8237 inhibits bladder cancer tumor growth when administered orally in a mouse bladder cancer xenograft model . Furthermore, MLN8237 potently inhibits proliferation of tumor stem‐like cells and potentiates the effects of temozolomide and ionizing radiation in glioblastoma …”

“…Indeed, Aurora-A inhibition has been shown to impair stem-like functions in various malignancies including ovarian cancer, 54 AML, 79 CML, 42 breast cancer, 81 glioma, 82 and glioblastoma. 83,84 The interaction between Aurora-A and Wntβ-catenin pathway is involved in CSC regulation in both CML and head and neck cancer. 85 In these cases, the β-catenin/TCF4 complex transcriptionally activates AURKA, and Aurora-A in turn inhibits GSK3β, stabilizes β-catenin, and further strengthens the core signaling for stemness.…”