Targeting IRAK4 with Emavusertib in Lymphoma Models with Secondary Resistance to PI3K and BTK Inhibitors

Abstract

Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) represent a recognized option for the treatment of patients affected by indolent B cell lymphomas. However, small molecules as single agents show limited success in their ability in inducing complete responses, with only partial remission achieved in most patients, suggesting the need for combination therapies. IRAK4 is a protein kinase downstream of the Toll-like receptor signaling (TLR), a driver pathway of secondary tumor° resistance in both hematological and solid tumor malignancies. Activation of IRAK4 upon TLRs and IL-1 receptor (IL-1R) stimulation and through the adaptor protein MYD88 initiates a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NF-κB. MYD88-L265P encoding mutations occur in diffuse large B-cell lymphomas, in lymphoplasmacytic lymphomas and in few marginal zone lymphomas (MZL). The IRAK4 inhibitor emavusertib (CA-4948) has shown early safety and clinical activity in lymphoma and leukemia patients. In this preclinical study, we assessed emavusertib effectiveness in MZL, both as single agent and in combination with targeted agents, with a particular focus on its capability to overcome resistance to BTK and PI3K inhibitors. We showed that the presence of MYD88 L265P mutation in bona fide MZL cell lines confers sensitivity to the IRAK4 inhibitor emavusertib as single agent. Emavusertib-based combinations improved the sensitivity of MZL cells to BTK and PI3K inhibitors, including cells with a secondary resistance to these agents. Emavusertib exerted its activity via inhibition of NF-κB signaling and induction of apoptosis. Considering the early safety data from clinical trials, our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored in trials for patients with MYD88-mutated indolent B cell lymphomas as single agent and as combination partner with BTK or PI3K inhibitors in unselected populations of patients.

MyD88 and Its Inhibitors in Cancer: Prospects and Challenges

“…Compared with MyD88 wild-type (WT), the TIR domain, where the MyD88 L265P mutation is located, is highly activated, resulting in enhanced downstream signaling and Myddosome complex formation. Although the MyD88 L265P mutation occurs in more than 90% of WM cases, this mutation is not WM-specific and is also observed in other DLBCLs, lymphoplasmacytic lymphomas, and a few marginal area lymphomas [35]. These results suggest that MyD88 mutation is associated with the occurrence of multiple tumors.…”

IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies

“…In B-cell NHL, emavusertib has shown synergy with covalent BTK inhibitors such as ibrutinib and with PI3K pathway inhibitors such as idelalisib and copanlisib (68,74). However, most patients ultimately develop resistance to covalent BTK inhibitors and PI3K inhibitors (38,84).…”

“…However, most patients ultimately develop resistance to covalent BTK inhibitors and PI3K inhibitors (38,84). While emavusertib has shown efficacy when combined with ibrutinib and PI3K inhibitors even in patients with secondary resistance to these agents (68), there is rationale to combine emavusertib with next generation inhibitors of the BTK pathway such as non-covalent BTK inhibitors and BTK degraders given the impressive efficacy of these agents in several heavily pretreated B-cell NHL patients that developed disease progression after prior treatment with a covalent BTK inhibitor and even prior PI3K inhibitors (85, 86). Inhibition of additional proteins in the BCR pathway such as SYK have shown pre-clinical efficacy when combined with emavusertib in B-cell NHL (42).…”

“…Furthermore, emavusertib blocked IL-1R stimulated cytokine production in these cells (66). In MZL cell lines, emavusertib treatment (10 mM) for 72 hours decreased the percentage of proliferating cells and induced a moderate increase in the sub-G0 fraction as evaluated by flow cytometry (68). Emavusertib (10 mM, 72 h) induced a significant increase in the apoptotic cell population, particularly when combined with ibrutinib compared to ibrutinib and emavusertib alone.…”

“…Emavusertib (10 mM, 72 h) induced a significant increase in the apoptotic cell population, particularly when combined with ibrutinib compared to ibrutinib and emavusertib alone. Decreased viability upon treatment with emavusertib was paired with a significant increase in apoptotic cells in both ibrutinib sensitive and ibrutinib resistant MZL cell lines (68).Thus, the mechanism of action of emavusertib is its binding and inhibition of IRAK-4 resulting in blockade of the MYD88 signaling pathway.…”