Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma
2019
Autori:
Nešović, MarijaMilošević, Zorica
Banković, Jasna
Tsimplouli, Chrisiida
Sereti, Evangelia
Dragoj, Miodrag
Podolski-Renić, Ana
Stanković, Tijana
Jovanović, Mirna
Dimas, Kostantinos
Pešić, Milica
Dinić, Jelena
Tip dokumenta:
Konferencijski prilog (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Resistance to chemotherapeutic agents represents a major issue in anticancer therapy.
Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its aggressive behavior and
resistance to treatment. Alterations in the PI3K/AKT/mTOR pathway and/or high expression
of ATP binding cassette transporters, such as P-glycoprotein and breast cancer resistance
protein (BCRP), are frequently linked to chemo-resistance. Autophagy is a key player in the
metabolic and therapeutic stress response and represents a potential target for anticancer
therapy. Autophagy induction in response to chemotherapeutics may contribute to both
drug efficacy as well as drug resistance. We assessed the therapeutic efficacy of dual mTOR
kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX) in combination in ATC cells. Rhocell line was generated from parental human thyroid carcinoma 8505C via the selection of cells with a low accumulation of rhodamine 123 (P-glycoprotein and BCRP substrate). Rhocells were 10-fold more resistant to PTX compared to 8505C cells and more tumorigenic. Both vistusertib and PTX induced autophagosome formation in the investigated cell lines. In combination, vistusertib sensitized Rho- cells to PTX via autophagy induction and proliferation inhibition, indicating a synergistic effect between the two compounds. Additionally, vistusertib and PTX combination in Rho- and 8505C cells inhibited cell migration
and invasion in vitro. Furthermore, vistusertib and PTX combination effectively suppressed
tumor growth of ATC xenografts in immunodeficient NSG mice in vivo. Considering chemoresistance and high invasive properties of ATC, described combined approach could be useful for the design of novel targeted treatment strategies in this malignancy
Finansiranje / projekti:
- Identifikacija molekularnih markera za predikciju progresije tumora, odgovora na terapiju i ishoda bolesti (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
U:
- Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria. COST Action CA1513; 2019. p. 30.