Dataset Information

The AKT inhibitiontor capivasertib potentiates the efficacy of the BTK inhibitor inhibitor and anti-CD20-based therapeutic regimens acalabrutinib in preclinical models of ABC-DLBCL

ABSTRACT: Relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell malignancy that has inadequate treatment options. BTK inhibitors such as acalabrutinib have demonstrated preclinical and clinical activity in the activated B-cell (ABC) DLBCL subset however tumour responses are modest resulting in short-term tumour control. To understand what limits BTK inhibits signaling mediated resistance was explored in vitro. BTK inhibition delivered through siRNA-mediated BTK down regulation or acalabrutinib treatment identified of AKT as a candidate resistance driver. In vitro combination of acalabrutinib with the AKT inhibitor capivasertib increased cell death in ABC-DLBCL cell lines, TMD8 and OCI-LY10. In vivo the combination benefit in resulted in tumor regressions in TMD8, OCI-LY10 tumor xenografts and stasis in an ABC-DLBCL PDX tumor which was associated with a reduction of S6 kinase phosphorylation and suppression of mTORC1 signaling gene expression. Notably RNA sequencing analysis of TMD8 cells and xenograft tumors revealed an enhancement of MS4A1 (CD20) gene expression following combination treatment in surviving cells. Adding rituximab to the combination further augmented in vivo efficacy driving to persistent tumor regressions of TMD8 tumours that were sustained following dosing cessation. In ABC-DLBCL targeting the BTK inhibitor induced feedback AKT reactivation can enhance efficacy, and furthermore, the combination of acalabrutinib and capivasertib primes tumor cells for CD20 targeted therapy with potential to deliver long-term durable responses in ABC-DLCBL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE344915 | GEO | 2026/09/05

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

Dataset Information

The AKT inhibitiontor capivasertib potentiates the efficacy of the BTK inhibitor inhibitor and anti-CD20-based therapeutic regimens acalabrutinib in preclinical models of ABC-DLBCL

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets