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|Ref Type||Journal Article|
|Authors||Tarantelli C, Gaudio E, Arribas AJ, Kwee I, Hillmann P, Rinaldi A, Cascione L, Spriano F, Bernasconi E, Guidetti F, Carrassa L, Pittau RB, Beaufils F, Ritschard R, Rageot D, Sele A, Dossena B, Rossi FM, Zucchetto A, Taborelli M, Gattei V, Rossi D, Stathis A, Stussi G, Broggini M, Wymann MP, Wicki A, Zucca E, Cmiljanovic V, Fabbro D, Bertoni F|
|Title||PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2018 01 01|
|Abstract Text||Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120-9. ©2017 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|PQR309||PQR 309|bimiralisib||mTOR Inhibitor 51 PI3K Inhibitor (Pan) 37||PQR309 (bimiralisib) is a dual pan-PI3K and mTORC1/2 inhibitor, which blocks PI3K/mTOR signaling, potentially resulting in inhibition of tumor growth (PMID: 29066507).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||lymphoma||not applicable||PQR309 + Rituximab||Preclinical - Cell culture||Actionable||In a preclinical study, the combination therapy of PQR309 and Rituxan (rituximab) led to a synergistic effect in 2/5 lymphoma cell lines in culture (PMID: 29066507).||29066507|
|Unknown unknown||diffuse large B-cell lymphoma||not applicable||Ibrutinib + PQR309||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination therapy of PQR309 and Imbruvica (ibrutinib) led to a synergistic effect in 6/7 diffuse large B-cell lymphoma (DLBCL) cell lines in culture, and the effect was confirmed in a DLBCL cell line xenograft model (PMID: 29066507).||29066507|
|Unknown unknown||lymphoma||not applicable||PQR309 + Venetoclax||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination therapy of PQR309 and Venclexta (venetoclax) led to antitumor activity in lymphoma cells in culture and cell line xenograft models, demonstrating both synergistic and additive effects (PMID: 29066507).||29066507|
|Unknown unknown||lymphoma||not applicable||Panobinostat + PQR309||Preclinical - Cell culture||Actionable||In a preclinical study, the combination therapy of Farydak (panobinostat) and PQR309 induced apoptosis and led to synergistic and additive effects in lymphoma cell lines in culture (PMID: 29066507).||29066507|
|Unknown unknown||lymphoma||not applicable||PQR309||Preclinical - Cell culture||Actionable||In a preclinical study, PQR309 inhibited proliferation of lymphoma cells in culture, which was found to be due to the induction cell cycle arrest (PMID: 29066507).||29066507|