We used next-generation technologies to understand the mechanisms governing resistance to clinical interventions in human cancer, in cells treated with a growth factor inhibitor and in cells exposed to doxorubicin. We identified Kmt2b as a differentially expressed gene in both resistant contexts. Kmt2b activation following both growth factor inhibition and doxorubicin chemotherapy suggested the presence of an epigenetic event involving Kmt2b in the context of challenging or stressful cellular situations .