{
  "abstract": "Casitas B lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that serves as a critical brake on immune cell activations. It negatively fine-tunes immune responses through ubiquitination of signaling proteins. Cbl-b deficiency in mice leads to spontaneous tumor rejection and induces only mild, non-lethal autoimmunity, highlighting its potential as a promising immunotherapy target. NX-1607 is the first oral small molecule inhibitor of Cbl-b and it is currently in phase I clinical trial. A recent publication employed high-throughput drug combination screening to systematically elucidate the molecular pathways by which NX-1607 enhances T cell activation. The authors administered 81 well-characterized inhibitors to Jurkat T cells under CD3-stimulated and unstimulated conditions in the presence of NX-1607. Inhibitors of the MAPK/ERK pathway significantly attenuated NX-1607-enhanced T cell activation as indicated by CD69 markers. Proto-oncogene tyrosine-protein kinase Src (SRC) family kinase inhibitors also reduced both CD69 activation markers and the phosphorylation of PLCγ1 and HCLS1 which are upstream of MAPK/ERK pathways. These findings were validated in an immunocompetent B-cell lymphoma mouse model, where NX-1607 consistently upregulated PLCγ1 and ERK phosphorylation. Together, this work delineates a PLCγ1-MAPK/ERK axis through which Cbl-b inhibition unleashes T cell activation, providing critical insight for the development of NX-1607 based immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong"
      ],
      "name": "Alex To"
    },
    {
      "affiliations": [
        "School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong",
        "Centre for Translational Stem Cell Biology, University of Hong Kong, Hong Kong, Hong Kong"
      ],
      "name": "Ryohichi Sugimura"
    }
  ],
  "title": "NX-1607: lifting the Cbl-b brake to promote T cell activation through MAPK/ERK pathways",
  "uid": "e54e9867-4a1b-5c97-9357-feb285e46033"
}