Acquired drug resistance is the main cause for disease relapse in cancer patients. One of the most important mechanisms leading to acquired drug resistance is the acquisition of genetic mutations leading to heterogeneity and growth advantage. In addition recent reports point to an adaptive more generic process resulting in permanent resistance. The transition from a drug-sensitive state to drug tolerant is characterized by an epigenetically driven distinct H3K4me3 slow cycling growth arrested reversible drug tolerant state in cancer cells preceding permanent resistance. The epigenetic dynamics behind the switch from the growth arrested state to acquired permanent resistance remain unknown. We show that persistent exposure to targeted- or chemotherapy in melanoma cells results in a state-dependent transition to drug resistance from parental cells to slow cycling low H3K4me3 and to multi- clonal cellular clusters capable of proliferation in the presence of the drug. Cells in these clusters regain H3K4me3 with concomitant expression of embryonic stem cell markers leading to the formation of permanent drug resistant cells through H3K4me3 mediated transcriptional regulation. Downregulation of AMPK activation through shRNA or inhibitors blocks H3K4me3 recovery and selectively ablates the formation of clusters thereby preventing acquired drug resistance and relapse of tumor growth. Identifying and targeting drivers behind this epigenetically forced transition prevents permanent resistance facilitating sustained remission in melanoma patients.