301 OMX-0407, a highly potent SIK3 inhibitor, sensitizes tumor cells to apoptosis and eradicates tumors in combination with PD-1 inhibition

Abstract

BackgroundInterference with post-translational modifications such as methylation and acetylation of DNA and histones may enhance the intrinsic anti-tumor capacity of the immune system. Using the iOTarg genetic screening platform, salt-inducible kinase 3 (SIK3) was recently identified as a novel immune checkpoint that controls T cell-mediated apoptosis in tumor cells. SIK3, a serine/threonine kinase of the AMPK family, regulates pro-survival gene expression in tumor cells through epigenetic modulation of the NF κB-driven gene landscape via histone deacetylase 4 (HDAC4), causing the tumor to evade T cell-mediated killing.MethodsIn turn, SIK3 knockout or knockdown abates downstream pro-survival signaling and sensitizes a panel of murine and human tumor cells to death receptor-mediated apoptosis.OMX-0407, an orally available, single-digit nanomolar inhibitor of SIK3 was shown to effectively reduce TNF-induced HDAC4 phosphorylation and downstream NF-κB activity in a dose-dependent manner, thereby enhancing caspase-mediated apoptosis in murine and human tumor cell lines. Decreased intratumoral NF-κB activity was demonstrated in vivo with an MC38 NF κB-luc reporter cell line.ResultsInhibition of the pro-tumorigenic NF-κB pathway using OMX-0407 monotherapy translated into significant tumor growth inhibition (TGI) as well as prolonged survival in the highly infiltrated syngeneic murine colorectal carcinoma model MC38 (76% TGI). Moreover, OMX-0407 repolarized the tumor microenvironment (TME) by strongly reducing the number of regulatory T cells (T-regs) and M2-polarized macrophages in the tumor bed, while not affecting the peripheral T cell compartment. Thereby, exposure to OMX-0407 achieved a pronounced pro-inflammatory TME, characterized by a rise in activated cytotoxic T lymphocytes (CTL) and an increased CTL-to-T-reg ratio.Using the breast cancer mouse model EMT6, which represents an immune-excluded, cold tumor phenotype, we demonstrated that despite the minimal anti-tumor efficacy of OMX-0407 and anti-PD-1 monotherapy, respectively, upon combination treatment, both therapies synergize by combining apoptosis sensitization with a reduction in immunosuppressive TME and an increase in cytotoxic T cell activity. Combination treatment resulted in partial and complete tumor remissions in 60% of the animals, along with a significant prolongation of overall survival.ConclusionsIn summary, OMX-0407, a first-in-class oral SIK3 inhibitor, demonstrates potent monotherapy efficacy in a pro-inflammatory tumor setting by reshaping the immune compartment and sensitizing tumor cells to death receptor-mediated apoptosis. The ability of OMX-0407 to remodel an immunosuppressed TME in a generally cold tumor setting, harbors great clinical potential for OMX-0407 combination therapy with anti-PD-1/PD-L1 immune checkpoint blockade, specifically in patients with high unmet medical need who are resistant to current immune checkpoint inhibitor monotherapy.

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods

“…In addition, SIKs are also dysregulated in prostate cancer, ovarian cancer, lung cancer, breast cancer, and other cancers ( Du et al, 2016 ; Wein et al, 2018 ; Chen F. Y. et al, 2019 ), which indicates that SIKs are appealing pharmacological targets for treating cancer. Recently, numerous SIKs inhibitors have been developed and applied in the preclinical or clinical studies ( Heap et al, 2017 ; Jin et al, 2020 ), such as HG-9-91-01 ( Clark et al, 2012 ), KIN112 ( Clark et al, 2012 ), YKL-06-062 ( Mujahid et al, 2017 ), MRT67307, MRT199665, OMX-0407 ( Hartl et al, 2021 ), and ARN-3236 ( Supplementary Figure S1 ) ( Zhou et al, 2017 ). However, no specifically SIKs inhibitors have been clinically approved.…”