Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma
Creators
- 1. Institute for Biological Research "Siniša Stanković", University of Belgrade, Despota Stefana 142, Belgrade, 11060, Serbia
- 2. Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41110, Larissa, Greece
- 3. Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotića 1, Belgrade, 11000, Serbia
- 4. Institute for Oncology and Radiology of Serbia, Pasterova 14, Belgrade, 11000, Serbia
Description
Purpose Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated
with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate.
Methods Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies. Results Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion.
Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth.
Conclusions Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the
treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.
Notes
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Additional details
Related works
- Is identical to
- 10.1007/s13402-018-0380-x (DOI)
Funding
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome 41031
- Ministry of Education, Science and Technological Development