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.
journal_name
Proc Natl Acad Sci U S Aauthors
Scuoppo C,Wang J,Persaud M,Mittan SK,Basso K,Pasqualucci L,Rabadan R,Inghirami G,Grandori C,Bosch F,Dalla-Favera Rdoi
10.1073/pnas.1905239116subject
Has Abstractpub_date
2019-08-20 00:00:00pages
16981-16986issue
34eissn
0027-8424issn
1091-6490pii
1905239116journal_volume
116pub_type
杂志文章abstract::The importance of Gly-93 and Gly-94 in transmembrane segment M1 of the Na+,K+-ATPase for interaction with Na+ and K+ was demonstrated by functional analysis of mutants Gly-93-Ala and Gly-94-Ala. In the crystal structures of the Ca2+-ATPase, the corresponding residues, Asp-59 and Leu-60, are located exactly where M1 be...
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