Repurposing dasatinib for diffuse large B cell lymphoma

Proceedings of the National Academy of Sciences of the United States of America
Claudio ScuoppoRiccardo Dalla-Favera

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.

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Citations

Apr 16, 2020·Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association·Chunling ZengYuexiang Wang
Feb 12, 2020·Seminars in Cancer Biology·Vinayak PalveUwe Rix
Dec 22, 2020·Frontiers in Cell and Developmental Biology·Man ZhangMee-Hyun Lee
Oct 24, 2020·Nature Communications·Erwan BeauchampLuc G Berthiaume
Jul 25, 2021·Cancers·Dimitra MavridouMichalis Aivaliotis
Aug 31, 2021·Frontiers in Immunology·Stefanie N MeyerLaura Pasqualucci

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