Thus, in conclusion, our studies as presented here not only elaborate the important role of the NGFR-p53 feedback loop in maintaining stem-like phenotype of MIC cells and boosting their proliferation, renewal, and survival, but also provide evidence for co-targeting NGFR and MDMX or MDM2 as a potential therapeutic strategy for highly aggressive and drug-resistant MIC-derived melanoma. The gene discussed is MDM4; the disease is melanoma.