| Literature DB >> 31383760 |
Claudio Scuoppo1,2, Jiguang Wang3, Mirjana Persaud4, Sandeep K Mittan4, Katia Basso4,2, Laura Pasqualucci4,2, Raul Rabadan3, Giorgio Inghirami5, Carla Grandori6, Francesc Bosch4,7, Riccardo Dalla-Favera1,2,8,9.
Abstract
To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.Entities:
Keywords: DLBCL; PTEN; dasatinib
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Year: 2019 PMID： 31383760 PMCID： PMC6708382 DOI： 10.1073/pnas.1905239116
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205