Targeting IRAK4 in DLBCL: The Therapeutic Potential of CA-4948 in Xenograft Models

The study focuses on the role of IRAK4 kinase in the signaling pathways of toll-like receptor (TLR) and interleukin-1 receptor (IL-1R), which are crucial in various cell types. A mutation in the MYD88 adaptor protein, present in approximately 22% of diffuse large B cell lymphoma (DLBCL) cases, particularly the MYD88 L265P mutation, is linked to a poor prognosis due to continuous NF-κB signaling activation. This highlights the potential of IRAK4 inhibitors as a promising strategy for treating cancers with MYD88 mutations, such as DLBCL.

Researchers are developing CA-4948, an IRAK4 inhibitor, to treat hematological cancers with disrupted TLR/MYD88/IRAK4 signaling. The compound has shown to be selective and potent with in vivo activity in a TLR4-induced cytokine release model. It has favorable pharmacokinetic properties, good oral bioavailability, and tolerability in mice. Previous studies have demonstrated its dose-dependent efficacy in ABC-DLBCL MYD88-L265P xenograft tumor models using cell lines OCI-LY3 and OCI-LY10.

The study presents the results of CA-4948 tested in a panel of patient-derived DLBCL tumor xenograft mouse models. The compound showed significant efficacy in four out of five ABC-DLBCL models compared to other subtypes. It was also effective against ABC-DLBCL tumors with activating mutations in both TLR/IL-1R and BCR signaling pathways (MYD88 and CD79B double mutants). Notably, a single ABC-DLBCL model with a MYD88 L265P mutation and BCL6 translocation was resistant to CA-4948. However, a combination of ibrutinib and CA-4948 showed a synergistic effect in inhibiting tumor growth in this resistant model.

In conclusion, CA-4948 has demonstrated anti-tumor activity in ABC-type DLBCL models, including those with combined activating mutations in TLR/IL-1R and BCR pathways. This indicates the potential of IRAK4 kinase inhibition by CA-4948 as a single agent or in combination with BCR inhibitors for DLBCL treatment.

The study was presented at the American Association for Cancer Research Annual Meeting in 2017, with the abstract published in Cancer Research.