The mitogen-activated protein kinase pathway facilitates resistance to the src inhibitor dasatinib in thyroid cancer
Molecular Cancer Therapeutics, ISSN: 1538-8514, Vol: 15, Issue: 8, Page: 1952-1963
2016
- 21Citations
- 41Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations21
- Citation Indexes21
- 21
- CrossRef15
- Captures41
- Readers41
- 41
Article Description
Advanced stages of papillary and anaplastic thyroid cancer represent a highly aggressive subset, in which there are currently few effective therapies. We and others have recently demonstrated that c-SRC is a key mediator of growth, invasion, and metastasis, and therefore represents a promising therapeutic target in thyroid cancer. However, clinically, Src inhibitor efficacy has been limited, and therefore further insights are needed to define resistance mechanisms and determine rational combination therapies. We have generated four thyroid cancer cell lines with a greater than 30-fold increase in acquired resistance to the Src inhibitor dasatinib. Upon acquisition of dasatinib resistance, the two RAS-mutant cell lines acquired the c-SRC gatekeeper mutation (T341M), whereas the two BRAF-mutant cell lines did not. Accordingly, Src signaling was refractory to dasatinib treatment in the RAS-mutant dasatinibresistant cell lines. Interestingly, activation of the MAPK pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcame acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-SRC gatekeeper mutation and MAPK pathway signaling play important roles in promoting resistance to the Src inhibitor dasatinib. We further demonstrate that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84985911609&origin=inward; http://dx.doi.org/10.1158/1535-7163.mct-15-0702; http://www.ncbi.nlm.nih.gov/pubmed/27222538; http://mct.aacrjournals.org/cgi/doi/10.1158/1535-7163.MCT-15-0702; https://syndication.highwire.org/content/doi/10.1158/1535-7163.MCT-15-0702; https://aacrjournals.org/mct/article/15/8/1952/146094/The-Mitogen-Activated-Protein-Kinase-Pathway; https://dx.doi.org/10.1158/1535-7163.mct-15-0702
American Association for Cancer Research (AACR)
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