High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC
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Elodie Montaudon1, Rania El Botty1, Sophie Vacher2, Olivier Déas3, Adnan Naguez1, Sophie Chateau-Joubert4, Damien Treguer1, Ludmilla de Plater1, Leïla Zemoura5, Fariba Némati1, André Nicolas6, Alain Chapelier7, Alain Livartowski8, Stefano Cairo3, Catherine Daniel8, Marie Brevet9, Elisabetta Marangoni1, Didier Meseure6, Sergio Roman-Roman10, Ivan Bieche2,*, Nicolas Girard8,* and Didier Decaudin1,11,*
1 Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France
2 Department of Genetics, Institut Curie, Paris, France
3 Xentech, Evry, France
4 BioPôle Alfort, National Veterinary School of Alfort, Maisons Alfort, France
5 Department of Pathology, Hôpital Foch, Suresnes, France
6 Department of Tumor Biology, Institut Curie, Paris, France
7 Department of Thoracic Surgery, Hôpital Foch, Suresnes, France
8 Institut du Thorax Curie Montsouris, Institut Curie, Paris, France
9 CYPATH, Centre Léon Bérard, Lyon, France
10 Department of Translational Research, Institut Curie, PSL University, Paris, France
11 Department of Medical Oncology, Institut Curie, Paris, France
* These authors contributed equally to this work
|Didier Decaudin,||email:||[email protected]|
Keywords: NSCLC; Pi3K signalling pathway; mTORC1; RAD001 (everolimus); PLK1
Received: January 01, 2021 Accepted: March 15, 2021 Published: April 13, 2021
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.
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