Melanoma drug resistance, driven predominantly by dynamic heterogeneity, prevails in slow-cycling rather than proliferative tumour cells. We analyzed the transcriptome of the 3D-spheroid melanoma model, where the inner cell-layers are slow-cycling induced by the microenvironment, and the outer cell-layers remain proliferative. The differentially expressed genes (DEGs) and pathways affecting the spheroid cell cycle (inner cells vs. outer cells, IVO) were then correlated with transcriptomics findings in drug-naïve (drug-sensitive) vs. drug-exposed tolerant (TVS) and resistant (RVS) melanoma models. IVO, TVS, and RVS had 1303, 1286, and 1195 upregulated DEGs, respectively. This number was 974, 1797 and 890 for downregulated genes. IVO shared 14.7% (192 genes) of their upregulated DEGs and 36.6% (357 genes) of their downregulated DEGs with the ones from TVS group. This number was 9.2% (120 genes) and 15.8% (154 genes) with DEGs from RVS group. Although some pathways, such as ‘lysosomal lumen’, showed to be enriched in upregulated DEGs in all three groups, the number of shared enriched pathways in IVO and TVS were higher than IVO and RVS. In addition, the miRNA analysis revealed that 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 this miRNA plays a key role in the 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 cell layers to hypoxia, characterized by upregulation of genes like VEGFA, NFKB2, and FOSL1, mirrors stable resistance (RVS), which focuses on maintaining critical survival pathways and reducing cell migration and invasion. In conclusion, environmentally stressed inner cell-layers revealed gene expression patterns more similar to drug-induced early persister than irreversibly drug-resistant cells.