ABSTRACT
The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK's kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.
Subject(s)
Benzimidazoles , Extracellular Signal-Regulated MAP Kinases , Myeloid Differentiation Factor 88 , Myeloid Differentiation Factor 88/metabolism , Myeloid Differentiation Factor 88/genetics , Humans , Animals , Mice , Extracellular Signal-Regulated MAP Kinases/metabolism , Cell Line, Tumor , Benzimidazoles/pharmacology , Apoptosis/drug effects , Immunogenic Cell Death/drug effects , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/metabolism , Female , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/immunology , Xenograft Model Antitumor Assays , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic useABSTRACT
Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further exploring its therapeutic potential. Here, we report the discovery of AB668, an outstanding selective inhibitor that binds CK2 through a bivalent mode, interacting both at the ATP site and an allosteric αD pocket unique to CK2. Using caspase activation assay, live-cell imaging, and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to representative ATP-competitive inhibitors, CX-4945, and SGC-CK2-1. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668, by targeting the CK2 αD pocket, has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death in several cancer cell lines and stimulating distinct biological pathways in renal cell carcinoma.