Oncotarget

Research Papers:

High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC

Elodie Montaudon, Rania El Botty, Sophie Vacher, Olivier Déas, Adnan Naguez, Sophie Chateau-Joubert, Damien Treguer, Ludmilla de Plater, Leïla Zemoura, Fariba Némati, André Nicolas, Alain Chapelier, Alain Livartowski, Stefano Cairo, Catherine Daniel, Marie Brevet, Elisabetta Marangoni, Didier Meseure, Sergio Roman-Roman, Ivan Bieche, Nicolas Girard and Didier Decaudin _

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Abstract

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

Correspondence to:

Didier Decaudin,email: Didier.decaudin@curie.fr

Keywords: NSCLC; Pi3K signalling pathway; mTORC1; RAD001 (everolimus); PLK1

Received: January 01, 2021     Accepted: March 15, 2021     Published: April 13, 2021

Copyright: © 2021 Montaudon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

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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