A point mutation in the BRAF gene, leading to a constitutively active form of the protein, is present in 45%-60% of patients and acts as a key driver in melanoma.,Shortly after therapy induction, resistance to MAPK pathway-specific inhibitors develops, indicating that pathway inhibition is circumvented by epigenetic mechanisms.,Here, we mimicked epigenetic modifications in melanoma cells by reprogramming them into metastable induced pluripotent cancer cells (iPCCs) with the ability to terminally differentiate into non-tumorigenic lineages. iPCCs and their differentiated progeny were characterized by an increased resistance against targeted therapies, although the cells harbor the same oncogenic mutations and signaling activity as the parental melanoma cells.,Furthermore, induction of a pluripotent state allowed the melanoma-derived cells to acquire a non-tumorigenic cell fate, further suggesting that tumorigenicity is influenced by the cell state.,•Human melanoma cells reprogrammed toward an iPSC-like state (iPCCs)•iPCCs differentiated into neurons and fibroblasts•iPCC-derived fibroblasts show no tumorigenic potential•iPCCs and iPCC-derived fibroblasts lose oncogene addiction,Human melanoma cells reprogrammed toward an iPSC-like state (iPCCs),iPCCs differentiated into neurons and fibroblasts,iPCC-derived fibroblasts show no tumorigenic potential,iPCCs and iPCC-derived fibroblasts lose oncogene addiction,Aberrant activation of the MAPK pathway is a major cause of melanoma.,Resistance to MAPK pathway-specific inhibitors hampers successful treatment of melanoma.,By reprogramming human melanoma cells toward pluripotency and subsequent differentiation, Utikal and colleagues demonstrate that the tumorigenic phenotype and oncogene addiction are linked to a certain differentiation lineage.
Response to targeted therapies varies significantly despite shared oncogenic mutations.,Nowhere is this more apparent than in BRAF(V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace.,Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs) though the underlying mechanisms have been largely uncharacterized.,Here, we found that EGFR induced vemurafenib resistance is ligand dependent.,We then employed whole-genome expression analysis and discovererd that vemurafenib resistance correlated with the loss of MITF, along with its melanocyte lineage program, and with the activation of EGFR signaling.,An inverse relationship between MITF, vemurafenib resistance and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients’ tumor specimens.,Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype.,In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors.,These findings indicate that an “autocrine drug resistance loop” is suppressed by melanocyte lineage signal(s), such as MITF.,This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.