GSE236239 Novel spirocyclic dimer, SpiD3, targets critical tumor survival pathways and displays potent preclinical activity in B-cell chronic lymphocytic leukemia

Contributors : Alexandria P Eiken ; Achyuth Kalluchi ; Jordan Rowley ; Dalia El-GamalSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensChronic lymphocytic leukemia (CLL) cell survival and growth is fueled by aberrant activation of various pro-survival signaling pathways within tumor niches. Specifically, B-cell receptor (BCR) signaling, toll-like receptor signaling, and supportive cellular interactions drive constitutive activation of NF- κB signaling and transcription of proliferative/pro-survival genes. Directly targeting the NF-κB pathway has been a challenge, however, herein, we investigated SpiD3, a spirocyclic dimer and novel NF-κB pathway inhibitor in preclinical models of CLL. Through cross-linking NF-κB proteins, SpiD3 a ttenuated NF-κB signaling in CLL cells independent of microenvironmental signals. Our integrated multi-omics and functional analyses revealed BCRNF-κB signaling, endoplasmic reticulum stress, oxidative stress, and activation of the unfolded protein response among the top pathways modulated by S piD3 treatment. This was accompanied by marked inhibition of global protein synthesis, cumulating in profound anti-tumor properties in CLL cells. SpiD3 also modulated tumor microenvironment interactions shown by decreased chemokine and cytokine gene expression as well as decreased CLL chemotaxis tow ards CXCL-12 and CXCL-13. Moreover, SpiD3 induced apoptosis of stroma-protected primary CLL cells comparable to th...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research