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In search of microenvironmental factors that keep dormant lung\u2010metastasizing neuroblastoma cells and brain\u2010metastasizing melanoma cells (BMMC) in check, we identified the beta subunit of hemoglobin and a heterodimer of alpha and beta chains of hemoglobin (\u03b1\/\u03b2 dimer) in the lung and brain microenvironments, respectively, as anti\u2010metastatic factors. A previous study demonstrated that the \u03b1\/\u03b2 dimer triggers programmed cell death of BMMC and downregulates the expression of BRD4, GAB2, and IRS2 proteins, which perform essential functions in tumorigenesis and progression. The working hypothesis of the present study is that in addition to its tumoricidal function, the \u03b1\/\u03b2 dimer serves as a pathfinder for the identification of therapy targets for BMMC. We, therefore, employed small\u2010molecule inhibitors of Bromodomain\u2010containing protein 4 (BRD4), GRB2\u2010associated\u2010binding protein 2 (GAB2), and Insulin receptor substrate 2 (IRS2) as potential anti\u2010BMMC agents. A combination of sub\u2010lethal concentrations of BRD4 and IRS2 inhibitors synergistically arrested BMMC at the subG1 phase of the cell cycle and killed more than 70% of BMMCs. The BRD4\/IRS2 inhibitor cocktail (designated hereafter as BRIRi) moderated the malignancy of BMMC lines from four different human melanomas. Preliminary results suggest that the BRIRi modulated \u201ccold\u201d BMMC to \u201chot\u201d ones. Among the top enriched functions of differentially expressed genes identified by RNAseq of BRIRi\u2010treated versus control BMMC, TNF and apoptotic signaling pathways were observed. We propose that co\u2010targeting BRD4 and IRS2 offers a promising approach for treating BMMC.<\/jats:p>","DOI":"10.1002\/ijc.35458","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T09:37:18Z","timestamp":1745660238000},"page":"773-787","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A heterodimer of hemoglobin identifies theranostic targets on brain\u2010metastasizing melanoma cells"],"prefix":"10.1002","volume":"157","author":[{"given":"Maharrish","family":"Chelladurai","sequence":"first","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research George S. Wise Faculty of Life Science, Tel Aviv University  Tel Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orit","family":"Sagi\u2010Assif","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research George S. 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