High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC
| Autor: | Leila Zemoura, Damien Treguer, Nicolas Girard, Marie Brevet, A. Chapelier, Didier Decaudin, Olivier Deas, Sophie Chateau-Joubert, Stefano Cairo, Rania El Botty, Sergio Roman-Roman, André Nicolas, Didier Meseure, Ivan Bièche, Sophie Vacher, Ludmilla de Plater, Elodie Montaudon, Elisabetta Marangoni, Catherine Daniel, Fariba Nemati, Adnan Naguez, Alain Livartowski |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Everolimus business.industry Volasertib mTORC1 Carbonic Anhydrase 9 medicine.disease 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Oncology chemistry In vivo 030220 oncology & carcinogenesis Cancer research Medicine Adenocarcinoma business Protein kinase B PI3K/AKT/mTOR pathway medicine.drug |
| Zdroj: | Oncotarget. 12:859-872 |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.27930 |
| Popis: | Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient's outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An in vivo study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1, CXCR4, and AXL. We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients. |
| Databáze: | OpenAIRE |
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