Second-generation BET degrader plus HDAC3-specific inhibition (dBET6 + BG45) was highly effective in metastasis-lineage colon cancer cells, exhibiting marked downregulation of ERCC2 in monolayers, spheroids, and xenografts, coinciding with antitumor outcomes in vivo. The gene discussed is DNER; the disease is malignant colon neoplasm.