Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas

• Published in: Cancer cell Vol. 42; no. 5; pp. 833 - 849.e12
• Main Authors: Choi, Jaewoo, Ceribelli, Michele, Phelan, James D., Häupl, Björn, Huang, Da Wei, Wright, George W., Hsiao, Tony, Morris, Vivian, Ciccarese, Francesco, Wang, Boya, Corcoran, Sean, Scheich, Sebastian, Yu, Xin, Xu, Weihong, Yang, Yandan, Zhao, Hong, Zhou, Joyce, Zhang, Grace, Muppidi, Jagan, Inghirami, Giorgio G., Oellerich, Thomas, Wilson, Wyndham H., Thomas, Craig J., Staudt, Louis M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.05.2024
• Subjects: ABC; B cell receptor; combination therapy; CSK; dexamethasone; DLBCL; GCB; glucocorticoids; PI3 kinase; prednisone; dexamethasone; DLBCL; ABC; PI3 kinase; GCB; combination therapy; CSK; glucocorticoids; B cell receptor; prednisone
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2024.04.007

Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK. [Display omitted] •Dampening oncogenic BCR signaling is a key anti-lymphoma action of glucocorticoids•The glucocorticoid receptor directly transactivates genes promoting BCR degradation•The glucocorticoid receptor represses CSK, degrading BCR-proximal kinases•Glucocorticoids are mechanistically rational drugs in anti-lymphoma regimens For more than 70 years, glucocorticoids have been known to have clinical activity against lymphoid but not myeloid malignancies. Choi et al. resolve this conundrum by demonstrating that glucocorticoids kill lymphomas by inhibiting BCR signaling. These mechanistic insights enable rational combination of glucocorticoids with other targeted agents in anti-lymphoma regimens.