Change search
ReferencesLink to record
Permanent link

Direct link
Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. Gothenburg University.ORCID iD: 0000-0001-6782-6622
Show others and affiliations
2014 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, no 853Article in journal (Refereed) PublishedText
Abstract [en]

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 BRAFV600E (8505C) and RASG13R (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 BRAFV600E or RASG13R 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.

Place, publisher, year, edition, pages
BioMed Central, 2014. Vol. 14, no 853
Keyword [en]
RET, FAK, Thyroid cancer, Breast cancer, Estrogen receptor, Kinase inhibitor
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-179958DOI: 10.1186/1471-2407-14-853OAI: oai:DiVA.org:kth-179958DiVA: diva2:891065
Note

Qc 20160108

Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2016-01-08Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Dinér, Peter
By organisation
Organic Chemistry
In the same journal
BMC Cancer
Chemical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 44 hits
ReferencesLink to record
Permanent link

Direct link