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

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.