OncoTargets and Therapy (Sep 2020)
Lights and Shade of Next-Generation Pi3k Inhibitors in Chronic Lymphocytic Leukemia
Abstract
Andrea Visentin,1,2 Federica Frezzato,1,2 Filippo Severin,1,2 Silvia Imbergamo,1 Stefano Pravato,1 Leila Romano Gargarella,1 Sabrina Manni,1,2 Serena Pizzo,1,2 Edoardo Ruggieri,1,2 Monica Facco,1,2 Anna Maria Brunati,3 Gianpietro Semenzato,1,2 Francesco Piazza,1,2 Livio Trentin1,2 1Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy; 2Veneto Institute of Molecular Medicine, Padua, Italy; 3Department of Molecular Medicine, University of Padua, Padua, ItalyCorrespondence: Livio TrentinHematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Via Giustiniani, 2 Padova, Padua 35128, ItalyTel +39 049 821 2298Fax +39 049 821 1970Email [email protected]: The treatment (i.e. therapy and management) of chronic lymphocytic leukemia (i.e. the disease) has been improved thanks to the introduction (i.e. approval) of kinase inhibitors during the last years. PI3K is one of the most important kinases at the crossroad to the B-cell receptor and cytokine receptor which play a key role in CLL cell survival, proliferation and migration. Idelalisib is the first in class PI3Kδ inhibitor approved for the treatment of relapsed/refractory CLL in combination with rituximab. Idelalisib activity in heavily treated patients is balanced by recurrent adverse events which limit its long-term use. These limitations prompt the investigation on novel PI3K inhibitors, also targeting different protein isoforms, and alternative schedule strategies. In this regard, duvelisib is the only PI3K γ and δ inhibitor approved as single agent for relapsed CLL. In this review, we will address novel insights on PI3K structure, isoforms, regulating signaling and the most updated data of next-generation PI3K inhibitors in CLL.Keywords: chronic lymphocytic leukemia, PI3K inhibitor, duvelisib, umbralisib, copanlisib
