Uloga mTOR i MAPK signalnih puteva u rezistenciji karcinoma štitaste žlezde na hemioterapiju
The role of mTOR and MAPK signaling pathways in resistance of thyroid carcinoma to chemotherapy.
2014
Authors:
Milošević, ZoricaContributors
Stamenković-Radak, MarinaBanković, Jasna
Tanić, Nikola
Pešić, Milica
Džodić, Radan
Document Type:
Doctoral thesis (Published version)
Metadata
Show full item recordAbstract:
Thyroid carcinoma is the most common malignancy of the endocrine system.
Thyroid malignancies are classified according to their histopathological characteristic
as papillary, follicular, medullary and anaplastic thyroid carcinoma (ATC). Most
thyroid malignancies (papillary thyroid carcinoma and follicular thyroid carcinoma)
are well differentiated and have favorable prognosis. On the other hand, ATC is one
of the most aggressive human cancers, with an intrinsic resistance and dismal
prognosis despite various therapeutic modalities. Changes in components of
RAS/MAPK/ERK and PI3K/AKT/mTORpathways are common in thyroid cancer
genesis which are resistant to classic chemotherapy agents. Changes in the activity of
RAS/MAPK/ERK and PI3K/AKT/mTORsignaling pathways can lead to drug
resistance. Besides these changes, possible cause of chemotherapy resistance is also
multi-drug resistance (MDR). The most common cause of MDR is high expression of
P-gp and BCRP proteins.
The aim of this study was to investigate the role of the key components of
RAS/MAPK/ERK and PI3K/AKT/mTOR pathways in the pathogenesis and
chemoresistance of ATC. We analyzed gene and protein changes in set of ATC
patient samples. We also investigated the role of inhibition of RAS/MAPK/ERK and
PI3K/AKT/mTOR pathways in ATC chemosensitization using human ATC cell lines.
The role of P-gp and BCRP proteins in ATC chemoresistance was also investigated.
Analysis of alterations in RAS/MAPK/ERK and PI3K/AKT/mTOR pathways
in ATC patients indicated that both pathways cooperate in the development of ATC.
Our results revealed a negative correlation between the activity of RAS/MAPK/ERK
and PI3K/AKT/mTOR pathways in the samples of ATC patients. NRAS oncogene and
p53 tumor suppressor are mutated with high frequency in our set of ATC samples.
NRAS is dominantly mutated gene, indicating the importance of this gene in ATC
development. All detected mutations in NRAS gene, and two mutations in p53 gene,
have never been reported in ATC genesis before.
In vitro results suggest that the inhibition of either RAS/MAPK/ERK or
PI3K/AKT/mTOR components may confer sensitivity of ATC cells to classic
chemotherapeutics. Treatment with dual mTOR inhibitor, AZD2014, alone or in
combination with paclitaxel (PTX) or doxorubicin (DOX) was shown to be the most
effective.
Immunohistochemical analysis showed high P-gp and BCRP expression in
our ATC samples, which indicates the role of these proteins in ATC chemoresistance.
We sorted ATC cells with the low Rhodamin123 (Rho123) accumulation which is
substrate of P-gp protein and established new ATC cell line. In this way we obtained
in vitro model system more similar to the patients’ phenotype, then comercial ATC
cell lines used in this study. We investigated the potential of dual mTOR inhibitor,
AZD2014 combined with PTX to sensitize this new ATC cell line. It was showed that
treatment with AZD2014 not only sensitizes ATC cells to PTX, but also combined
with this cytostatic, efficiently inhibits ATC cell migration and invasion. Taking into
account that chemoresistance and invasiveness of ATC are the main causes of poor
outcome, the application of dual mTOR inhibitor combined with PTX, seems to be a
logical therapeutic strategy for patients with ATC.
Keywords:
Anaplastic thyroid cancer (ATC); RAS/MAPK/ERK pathway; PI3K/AKT/mTOR pathway; ATC chemoresistance; ATC invasiveness; Dual mTOR; Inhibitor; AZD2014; Paclitaxel (PTX)Source:
University of Belgrade, Faculty of Biology, 2014, 1-122Funding / projects:
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
URI
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http://nardus.mpn.gov.rs/123456789/5283
https://radar.ibiss.bg.ac.rs/handle/123456789/2399