Enhancing B-Cell Lymphoma Treatment: Synergy of IRAK4, BTK, and PI3K Inhibitors

Interleukin receptor associated kinase 4 (IRAK4) signaling is implicated in the development of certain B-cell lymphomas and is upstream of the frequently mutated MYD88 gene, which is associated with malignancies such as diffuse large B-cell lymphoma (DLBCL) and Waldenström's macroglobulinemia (WM). IRAK4 signaling is also known to interact with other pathways including Bruton's tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K). Two novel IRAK1/4 inhibitors, LG0224912 and LG0250276, have been identified as potential treatments for B-cell lymphomas, showing high potency in kinase inhibition assays with IC50 values of 0.7 nM and 2.9 nM respectively. These compounds were confirmed as selective kinase inhibitors after being tested against a panel of 381 kinases.

The functional inhibition of the IL-1 pathway was evaluated using the A549 cell line, which has high IL-1R expression. Cells were treated with interleukin-1 and interleukin-6 (IL-6) levels were measured via ELISA, revealing that both compounds effectively inhibited IL-6 with an IC50 less than 100 nM.

The anti-proliferative effects of IRAK4 inhibitors were further studied in B-cell lymphoma cell lines, including those with the activating L265P mutation in MYD88 (OCI-LY3 and MWCL1) and those with wild type MYD88 (OCI-LY19 and U266). Across all cell lines, the inhibitors showed anti-proliferative activity with IC50s ranging from 300 nM to 10 μM. The activity was consistent across the different cell lines, and importantly, was not influenced by the presence of the MYD88 mutation.

Synergy studies were conducted combining IRAK4 inhibitors with either the BTK inhibitor ibrutinib or the PI3K inhibitors idelalisib and TGR-1202. The combination of LG0250276 with ibrutinib showed moderate synergism with a combination index (CI) of 0.67 in the OCI-LY19 cell line. More pronounced synergism was observed when LG0250276 was combined with idelalisib, yielding a CI of 0.25, and similar results were found with TGR-1202. These findings indicate that IRAK4 inhibition could enhance the therapeutic effects when used in combination with BTK or PI3K inhibitors for B-cell lymphomas, regardless of the MYD88 mutation status.

The study was presented by Eric G. Vajda, Robert Niecestro, Lin Zhi, and Keith B. Marschke at the 106th Annual Meeting of the American Association for Cancer Research in Philadelphia, PA, and published in Cancer Research 2015;75(15 Suppl):Abstract nr 785.