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

Élodie Montaudon ,Fariba Némati,Catherine Daniel,Elisabetta Marangoni,Didier Decaudin,Ludmilla De Plater,Alain Livartowski,Adnan Naguez,Didier Meseure,Alain Chapelier,Olivier Déas,André Nicolas,Marie Brevet,Sophie Vacher,Stefano Cairo,Nicolas Girard,Rania El Botty,Damien Treguer,Ivan Bièche ,L Zemoura ,Sergio Román-Román ,Sophie Château-Joubert

doi:10.18632/oncotarget.27930

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.

Highlights

Targeting the Pi3K signaling pathway in the treatment of non-small cell lung cancers (NSCLC) has been proposed for more than ten years
Two different therapies have been tested, i.e., the Pi3K inhibitor BKM120 and the mTORC1 inhibitor RAD001, in four Patient-Derived Xenografts (PDXs), two of them defined by a PI3KCA mutation (ML1 and ML5) and two by a KRAS mutation (LCF15 and LCF25)
Two different combinations have been tested: First, in one PDX defined by both PI3KCA and EGFR mutations, i.e., the LCF12 PDX, we have evaluated the efficacy of BKM120 + one EGFR-targeted therapy; we have observed no significant improvement of antitumor response after the three combinations in comparison to the most efficient monotherapy (Supplementary Figure 2), with a significant higher efficacy of afatinib in comparison to cetuximab and erlotinib (p < 10-2)

Summary

Introduction

Targeting the Pi3K signaling pathway in the treatment of non-small cell lung cancers (NSCLC) has been proposed for more than ten years. In the context of tumors defined by a Pi3K activation (PI3KCA or PTEN mutations), very few clinical trials have tested single-agent Pi3K signaling pathway, all of them showing a modest activity in molecularly unselected NSCLC patients [3], with the mTORC1 inhibitor everolimus (RAD001) [4], and the pan-Pi3K inhibitor Taselisib [5] or Buparlisib [6] Based on this rationale for the Pi3K pathway targeting in NSCLC, a huge number of clinical trials have tested various Pi3K-based combination of treatments, including chemotherapies such as pemetrexed [7, 8], taxanes [9,10,11,12,13], platinium salts [12,13,14], EGFRTKi (afatinib [15], erlotinib [16,17,18], or gefitinib [19, 20]), radiotherapy [14, 21,22,23], and others (sunitinib [24] and sunitinib [25]). Almost all of these combinations have been defined according to standard chemotherapies or NSCLC mutations, but not according to specific targets identified as biomarkers of resistance to Pi3K-targeting treatments

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