Through in-vitro pharmacological super-enhancer disruption assays, we confirmed that super-enhancers upregulate NSMCE2 and MAL2 transcriptionally, and, through bioinformatics, we found that high levels of NSMCE2 strongly associate with patients’ poor response to chemotherapy, especially for patients diagnosed with aggressive triple negative and HER2 positive tumor types. This evidence concerns the gene ERBB2 and neoplasm.