Montaudon Elodie, El Botty Rania, Vacher Sophie, Déas Olivier, Naguez Adnan, Chateau-Joubert Sophie, Treguer Damien, de Plater Ludmilla, Zemoura Leïla, Némati Fariba, Nicolas André, Chapelier Alain, Livartowski Alain, Cairo Stefano, Daniel Catherine, Brevet Marie, Marangoni Elisabetta, Meseure Didier, Roman-Roman Sergio, Bieche Ivan, Girard Nicolas, Decaudin Didier
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France.
Department of Genetics, Institut Curie, Paris, France.
Oncotarget. 2021 Apr 13;12(8):859-872. doi: 10.18632/oncotarget.27930.
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 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., , , and . 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 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.
在非小细胞肺癌（NSCLC）治疗中，针对PI3K/AKT/mTOR通路进行特异性靶向治疗有充分的理论依据。然而，几乎所有评估基于Pi3K通路的单一疗法/联合疗法的临床试验均未观察到患者预后的改善。因此，我们研究的目的是基于对mTORC1抑制剂RAD001/依维莫司耐药的预测标志物的测定来确定联合治疗方案。一项研究显示RAD001在NSCLC患者来源的异种移植瘤（PDXs）中具有高效性。通过RT-PCR研究观察耐药生物标志物时，发现有三个基因在耐药肿瘤中高表达，即 、 和 。然后我们将研究重点放在RAD001与PLK1抑制剂Volasertib的联合应用上，并观察到该联合疗法相较于单一疗法具有高抗肿瘤活性；同样，在一项 研究中发现这两种化合物之间有明显的协同效应。药效学研究表明，这种协同作用归因于：（1）肿瘤血管生成减少、HIF1蛋白表达增加以及细胞内pH值降低；（2）碳酸酐酶9（CAIX）蛋白减少，而这无法纠正细胞内酸中毒。总之，所有这些临床前数据强烈表明，抑制mTORC1和PLK1蛋白可能是NSCLC患者一种有前景的治疗方法。
