[HTML][HTML] Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide

AEA Lopez-Girona, D Mendy, T Ito, K Miller, AK Gandhi… - Leukemia, 2012 - nature.com
AEA Lopez-Girona, D Mendy, T Ito, K Miller, AK Gandhi, J Kang, S Karasawa, G Carmel…
Leukemia, 2012nature.com
Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in
hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon
(CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies
demonstrate that thalidomide, lenalidomide and another immunomodulatory drug,
pomalidomide, bound endogenous CRBN and recombinant CRBN–DNA damage binding
protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and …
Abstract
Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN–DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide-and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN YW/AA. Overexpression of CRBN wild-type protein, but not CRBN YW/AA mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21 WAF-1 expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
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