Author:
Scuoppo Claudio,Wang Jiguang,Persaud Mirjana,Mittan Sandeep K.,Basso Katia,Pasqualucci Laura,Rabadan Raul,Inghirami Giorgio,Grandori Carla,Bosch Francesc,Dalla-Favera Riccardo
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.
Publisher
Proceedings of the National Academy of Sciences
Cited by
21 articles.
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