Melanoma drug resistance, driven predominantly by dynamic heterogeneity, prevails in slow-cycling rather than proliferating tumour cells. We analyzed the transcriptome of 3D melanoma spheroids, where the inner cell-layers are slow-cycling while the outer cell-layers remain proliferating. The differentially expressed genes (DEGs) and pathways affecting the spheroid cell cycle (inner vs. outer cells, IVO) were correlated with drug-sensitive vs. drug-tolerant (TVS) and drug-resistant (RVS) melanoma. IVO shared 14.7% (192 genes) of their upregulated and 36.6% (357 genes) of their downregulated DEGs with the TVS group, and 9.2% (120 genes) and 15.8% (154 genes) with the RVS group. The number of shared enriched pathways in IVO vs. TVS was higher than IVO vs. RVS. In addition, hsa-miR-4497 is the only miRNA that is dysregulated significantly in all three experimental conditions. Our comparative analysis of hsa-miR-4497 target genes revealed it plays a key role in all three different experimental groups through distinct but overlapping mechanisms. We speculate that hsa-miR-4497 drives both inner and drug-tolerant cells to exhibit early adaptive responses to stress. Although through regulation of different genes in inner and resistant cells, the genes affected by hsa-miR-4497 exhibit long-term adaptive processes that involve a strategic reallocation of resources to enhance survival under prolonged adverse conditions. Also, adaptation of inner cells to hypoxia mirrors stable resistance (RVS), which focuses on maintaining critical survival pathways and reducing cell migration and invasion. In conclusion, environmentally stressed inner cells revealed gene expression patterns more similar to drug-induced early persister than irreversibly drug-resistant cells.