IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein, which is mutated in ~22% of DLBCL cases. The MYD88 L265P activating mutation is found in ~30% of the activated B-cell (ABC) and ~6% of germinal center B-cell (GCB) subtypes of DLBCL and leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. Thus, the development of small molecule inhibitors targeting IRAK4 is an attractive anticancer strategy for MYD88 mutation-containing cancers such as DLBCL.

We are developing an IRAK4 inhibitor, CA-4948, as a therapeutic agent for hematological cancers with dysregulated TLR/MYD88/IRAK4 signaling. CA-4948 (previously AU-4948) is a selective and potent IRAK4 kinase inhibitor with in vivo activity in a TLR4-induced cytokine release model. CA-4948 exhibits favorable DMPK properties, oral bioavailability, and is well tolerated in mice. Furthermore, CA-4948 was previously shown to exhibit dose-dependent efficacy in ABC-DLBCL MYD88-L265P xenograft tumor models using cell lines OCI-LY3 and OCI-LY10.

Here, we report the efficacy results from testing CA-4948 in a panel of well characterized, patient-derived DLBCL tumor xenograft (PDX) mouse models. CA-4948 exhibited the greatest efficacy in four of the five ABC-DLBCL PDX models tested as compared to GBC-DLBCL and ABC/GCB DLBCL PDX models. Furthermore, CA-4948 was efficacious in ABC-DLBCL PDX tumors containing activating mutations in both TLR/IL-1R and BCR signaling pathways (MYD88 and CD79B double mutants). Interestingly, the one ABC-DLBCL PDX model that failed to respond to CA-4948 treatment contained a MYD88 L265P mutation as well as a BCL6 translocation. While this particular PDX model was resistant to CA-4948, and showed a weak anti-tumor response to single-agent ibrutinib, the combination treatment of ibrutinib and CA-4948 exhibited a synergistic tumor growth inhibition effect. In summary, CA-4948 exhibited anti-tumor activity in ABC-type DLCBL PDX tumor models including those containing combinations of activating mutations in the TLR/IL-1R and BCR signaling pathways. These results underscore the therapeutic potential of IRAK4 kinase inhibition by CA-4948, as a single-agent or in combination with BCR inhibitors, for the treatment of DLBCL.

Citation Format: Robert N. Booher, Maria Elena Samson, Guang-Xin Xu, Hongsheng Cheng, David P. Tuck. Efficacy of the IRAK4 inhibitor CA-4948 in patient-derived xenograft models of diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1168. doi:10.1158/1538-7445.AM2017-1168