Trending with Impact: Promising NSCLC Therapeutic Approach: mTORC1 and PLK1 Inhibition

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Oncotarget

Oncotarget published this trending research paper on April 13, 2021, entitled, "High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC" by researchers from the Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France; Department of Genetics, Institut Curie, Paris, France; Xentech, Evry, France; BioPôle Alfort, National Veterinary School of Alfort, Maisons Alfort, France; Department of Pathology, Hôpital Foch, Suresnes, France; Department of Tumor Biology, Institut Curie, Paris, France; Department of Thoracic Surgery, Hôpital Foch, Suresnes, France; Institut du Thorax Curie Montsouris, Institut Curie, Paris, France; CYPATH, Centre Léon Bérard, Lyon, France; Department of Translational Research, Institut Curie, PSL University, Paris, France; Department of Medical Oncology, Institut Curie, Paris, France. 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. Press release - https://www.oncotarget.com/news/pr/mtorc1-and-plk1-inhibition-in-adenocarcinoma-nsclc/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27930 DOI - https://doi.org/10.18632/oncotarget.27930 Full text - https://www.oncotarget.com/article/27930/text/ Correspondence to - Didier Decaudin - Didier.decaudin@curie.fr Keywords - NSCLC, Pi3K signalling pathway, mTORC1, RAD001 (everolimus), PLK1 About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957