Omnipotent OMX-0370: Overcoming Tumor Immune Evasion through SIK3 Inhibition and TNF Sensitivity Restoration

The study highlights the role of SIK3, a serine/threonine kinase, in tumor cells' resistance to TNF, a common immune evasion mechanism in solid tumors. Approximately 70% of tested tumor cell lines showed resistance or proliferation upon TNF exposure. SIK3's deletion in PANC-1 and MC38 cells made them sensitive to TNF-induced death. SIK3's presence in tumors maintains HDAC4 in the cytoplasm, which keeps chromatin open and enhances NF-κB's pro-tumorigenic activity driven by TNF.

Researchers developed OMX-0370, a potent SIK3 inhibitor, which showed a dose-dependent decrease in HDAC4 phosphorylation and nuclear NF-κB activity in response to TNF. This treatment led to significant apoptosis in tumor cells, sparing non-TNF treated cells. In pharmacokinetic studies, OMX-0370 was orally bioavailable, well-tolerated, and displayed a favorable profile. It was tested in various tumor models, showing superior tumor growth inhibition compared to anti-PD-1 antibody treatment in certain models. Immune profiling revealed increased intratumoral T cell activation, improved CTL to Treg ratio, and reduced tumor-associated M2 macrophages without affecting peripheral leukocyte counts.

A reporter cell line was created to monitor OMX-0370's target engagement and pharmacodynamics, demonstrating its inhibitory effect on TNF-induced NF-κB activation. Given the promising results, follow-on variants of OMX-0370 with enhanced potency and in vivo exposure were developed.

The research concludes that OMX-0370 is an effective immunotherapeutic agent that neutralizes TNF-driven NF-κB activity in tumors, making them susceptible to TNF-induced apoptosis. It addresses the need for effective immunotherapies targeting key immune evasion pathways in solid tumors as a standalone treatment.