These preclinical data strongly suggest inhibition of mTORC1 or PLK1 proteins as a promising treatment option for NSCLC patientsOncotarget published "Highly in vitro, in vivo synergistic activities between mTORC1 inhibition and PLK1 inhibition adenocarcinoma NSCLC". It stated that the study's goal was to determine the best combination of treatments based on predictive markers of resistance to RAD001/Everolimus.Three genes were identified as high expression in resistant tumors by RT-PCR analysis.In vitro studies revealed a clear synergistic effect of the two compounds.The Pharmacodynamics study showed that this synergy was due in part to decreased tumor vascularization, increased HIF1 protein expression, decrease in intracellular pH and decreases of Carbonic Anhydrase 9 which could not correct intracellular acidsis.All these preclinical data strongly suggest inhibition of mTORC1 or PLK1 proteins as a promising treatment option for NSCLC patients.These preclinical data strongly suggest inhibition of mTORC1 or PLK1 proteins as a promising treatment option for NSCLC patientsDr. Didier Decaudin, from The Institut Curie, stated that "specifically targeting the Pi3K pathway in the treatment non-small cell lung carcinomas (NSCLC), has been proposed for over ten years."Surprisingly, however, few clinical trials have been conducted to test single-agent Pi3K signaling pathways in tumors that are defined by Pi3K activation. All of these agents showed modest activity in NSCLC patients with everolimus and the pan-Pi3K inhibitor Taselisib, Buparlisib.This is the reason for the Pi3K pathway to NSCLC. A large number of clinical trials have therefore tested various Pi3K combinations of treatments including chemotherapies like pemetrexed and taxanes as well as radiotherapy and EGFR-TKi.These combinations were almost all determined using standard chemotherapies and NSCLC mutations. However, they did not follow specific targets that have been identified as biomarkers for resistance to Pi3K targeted treatments.The principal strategy was to use a panel NSCLC PDXs to determine predictive markers of response and identify combinations of treatments that might be able reverse RAD001 resistance.Using two well-documented Pi3K and mTORC1 targeted therapies (BKM120 and RAD001), they first evaluated in vivo reactions in NSCLC patient-derived xenografts. Second, they identified a marker of resistance that could be pharmacologically proposed. Finally, they evaluated a new, more relevant combination of treatments.In their Oncotarget Research Output, the Decaudin Research Team concluded that there was no support for the determination of a relevant Pi3K therapeutic combination. This was due to the absence of molecular abnormalities or physician therapeutic practices. However, it was supported by the identification predictive markers of resistance against Pi3K monotherapies.This step-by-step method highlights the value of preclinical models for human cancers such as PDXs. It could be summarized as follows:Assessment and validation for antitumor activities of treatments X. Determination and validation for a predictive marker to resistance to the compound. X. Identification and validation of a second treatment, Y. Validation of its clinical relevance in terms prognostic impact. Lastly, clinical assessment of cancer patients.This method may encourage more clinical trials, avoid inefficient combinations, unacceptable toxicities, and save money and time.###DOI - https:/// doi. DOI - https:/ / doi. 18632/ oncotarget. 27930Full text available at https:////www. oncotarget. http:// oncotarget.com/ article/ 27930/text/Correspondence to Didier Decaudin, Didier.decaudin@curie.frKeywords: NSCLC, Pi3K signalling pathway and mTORC1, PLK1 and RAD001 (everolimus).About OncotargetOncotarget is an open-access bi-weekly peer-reviewed journal that covers all aspects of oncology.Visit https:/// / www.for more information about Oncotarget Oncotarget.com is a website that provides information about Oncotarget. Connect with:SoundCloud - https:/// / soundcloud. https:/ / soundcloud.Facebook - https:/// / www. facebook. facebook.com/ Oncotarget/Twitter - https:/// / twitter. https:/ / twitter.LinkedIn - https:/// / www. LinkedIn - https:/ / www.Linkedin. http://www.linkedin.com/company/oncotargetPinterest - https:/// / www. Pinterest. pinterest.Reddit - http:/ /www. reddit. reddit.com/ user/ Oncotarget/
