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01.04.2013 | PRECLINICAL STUDIES

Mechanisms of acquired resistance to insulin-like growth factor 1 receptor inhibitor in MCF-7 breast cancer cell line

verfasst von: Roudy Chiminch Ekyalongo, Toru Mukohara, Yu Kataoka, Yohei Funakoshi, Hideo Tomioka, Naomi Kiyota, Yutaka Fujiwara, Hironobu Minami

Erschienen in: Investigational New Drugs | Ausgabe 2/2013

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Summary

The purpose of this study was to clarify the mechanism of acquired resistance to the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor NVP-AEW541. We developed an acquired resistant model by continuously exposing MCF-7 breast cancer cells to NVP-AEW541 (MCF-7-NR). MCF-7 and MCF-7-NR were comparatively analyzed for cell signaling and cell growth. While phosphorylation of Akt was completely inhibited by 3 μM NVP-AEW541 in both MCF-7 and MCF-7-NR, phosphorylation of S6K remained high only in MCF-7-NR, suggesting a disconnection between Akt and S6K in MCF-7-NR. Consistently, the mTOR inhibitor everolimus inhibited phosphorylation of S6K and cell growth equally in both lines. Screening of both lines for phosphorylation of 42 receptor tyrosine kinases with and without NVP-AEW541 showed that Tyro3 phosphorylation remained high only in MCF-7-NR. Protein expression of Tyro3 was found to be higher in MCF-7-NR than in MCF-7. Gene silencing of Tyro3 using siRNA resulted in reduced cell growth and cyclin D1 expression in both lines. While Tyro3 expression was inhibited by NVP-AEW541 and everolimus in MCF-7, it was reduced only by everolimus in MCF-7-NR. These findings suggested that cyclin D1 expression was regulated in a S6K/Tyro3-dependent manner in both MCF-7 and MCF-7-NR, and that the disconnection between IGF-1R/Akt and S6K may enable MCF-7-NR to keep cyclin D1 high in the presence of NVP-AEW541. In summary, acquired resistance to NVP-AEW541 appears to result from IGF-1R/Akt-independent activation of S6K and expression of Tyro3 and cyclin D1.

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Titel: Mechanisms of acquired resistance to insulin-like growth factor 1 receptor inhibitor in MCF-7 breast cancer cell line
verfasst von: Roudy Chiminch Ekyalongo
Toru Mukohara
Yu Kataoka
Yohei Funakoshi
Hideo Tomioka
Naomi Kiyota
Yutaka Fujiwara
Hironobu Minami
Publikationsdatum: 01.04.2013
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 2/2013
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-012-9855-1

Springer Medizin

Mechanisms of acquired resistance to insulin-like growth factor 1 receptor inhibitor in MCF-7 breast cancer cell line

Summary

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