1. The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax
- Author
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Ivo Kwee, Filippo Spriano, Matthias P. Wymann, Emanuele Zucca, Florent Beaufils, Francesco Bertoni, Chiara Tarantelli, Luciano Cascione, Luca Aresu, Vladimir Cmiljanovic, Anastasios Stathis, Denise Rageot, Giulio Sartori, Doriano Fabbro, Petra Hillmann, and Eugenio Gaudio
- Subjects
0301 basic medicine ,Cancer Research ,mantle cell lymphoma ,lymphoma ,mTORC1 ,mTORC2 ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Protein kinase B ,PI3K/AKT/mTOR pathway ,venetoclax ,Venetoclax ,Kinase ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,diffuse large B cell lymphoma ,Lymphoma ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Diffuse large B-cell lymphoma - Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling cascade is an important therapeutic target for lymphomas. Rapamycin-derivates as allosteric mTOR complex 1 (TORC1) inhibitors have shown moderate preclinical and clinical anti-lymphoma activity. Here, we assessed the anti-tumor activity of PQR620, a novel brain penetrant dual TORC1/2 inhibitor, in 56 lymphoma cell lines. We observed anti-tumor activity across 56 lymphoma models with a median IC50 value of 250 nM after 72 h of exposure. PQR620 was largely cytostatic, but the combination with the BCL2 inhibitor venetoclax led to cytotoxicity. Both the single agent and the combination data were validated in xenograft models. The data support further evaluation of PQR620 as a single agent or in combination with venetoclax.
- Published
- 2019
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