Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86

BMC Cancer

John P Alao¹  Sona Michlikova¹  Peter Dinér²  Morten Grøtli¹  Per Sunnerhagen¹ 

[1] Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, SE-405 30 Göteborg, Sweden

[2] Present address: Department of Chemistry/Organic, KTH Royal Institute of Technology, Teknikringen 30, SE-100 44 Stockholm, Sweden

关键词: Kinase inhibitor;    Estrogen receptor;    Breast cancer;    Thyroid cancer;    FAK;    RET;   

Others  :  1118086
DOI  :  10.1186/1471-2407-14-853

 received in 2014-10-02, accepted in 2014-11-10,  发布年份 2014

【 摘 要 】

Background

The RET tyrosine kinase receptor has emerged as a target in thyroid and endocrine resistant breast cancer. We previously reported the synthesis of kinase inhibitors with potent activity against RET. Herein, we have further investigated the effect of the lead compound SPP86 on RET mediated signaling and proliferation. Based on these observations, we hypothesized that SPP86 may be useful for studying the cellular activity of RET.

Methods

We compared the effects of SPP86 on RET-induced signaling and proliferation in thyroid cancer cell lines expressing RET-PTC1 (TPC1), or the activating mutations BRAF^V600E (8505C) and RAS^G13R (C643). The effect of SPP86 on RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK pathway signaling and cell proliferation in MCF7 breast cancer cells was also investigated.

Results

SPP86 inhibited MAPK signaling and proliferation in RET/PTC1 expressing TPC1 but not 8505C or C643 cells. In TPC1 cells, the inhibition of RET phosphorylation required co-exposure to SPP86 and the focal adhesion kinase (FAK) inhibitor PF573228. In MCF7 cells, SPP86 inhibited RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling and estrogen receptorα (ERα) phosphorylation, and inhibited proliferation to a similar degree as tamoxifen. Interestingly, SPP86 and PF573228 inhibited RET/PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree.

Conclusion

SPP86 selectively inhibits RET downstream signaling in RET/PTC1 but not BRAF^V600E or RAS^G13R expressing cells, indicating that downstream kinases were not affected. SPP86 also inhibited RET signaling in MCF7 breast cancer cells. Additionally, RET- FAK crosstalk may play a key role in facilitating PTC1/RET and GDNF- RET induced activation of Akt and MAPK signaling in TPC1 and MCF7 cells.

【 授权许可】

   
2014 Alao et al.; licensee BioMed Central Ltd.

【 图 表 】

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