TY  - JOUR
A1  - Kollareddy, Madhu
A1  - Sherrard, Alice
A1  - Park, Ji Hyun
A1  - Szemes, Marianna
A1  - Gallacher, Kelli
A1  - Melegh, Zsombor
A1  - Oltean, Sebastian
A1  - Michaelis, Martin
A1  - Cinatl, Jindrich
A1  - Kaidi, Abderrahmane
A1  - Malik, Karim
T1  - The small molecule inhibitor YK-4-279 disrupts mitotic progression of neuroblastoma cells, overcomes drug resistance and synergizes with inhibitors of mitosis
T2  - Cancer letters
N2  - Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers.
KW  - Neuroblastoma
KW  - Chemotherapy
KW  - YK-4-279
KW  - Mitosis
KW  - Drug resistance/synergy
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44745
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-447457
SN  - 1872-7980
SN  - 0304-3835
N1  - © 2017 The Author(s). Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
VL  - 403
SP  - 74
EP  - 85
PB  - Elsevier Science
CY  - Amsterdam [u. a.]
ER  -