Deregulated Fasn Expression In Braf Inhibitor-Resistant Melanoma Cells Unveils New Targets For Drug Combinations

Simple SummaryStrategies to overcome resistance to targeted therapy represent a clinical need for metastatic melanoma. Altered lipid metabolism has been identified in the metabolic reprogramming associated with melanoma progression. Lipid metabolism genes such as fatty acid synthase (FASN) and 24-dehydrocholesterol reductase (DHCR24) have been proposed to contribute to tumor aggressiveness, but the therapeutic value of lipid metabolism inhibitors, particularly in drug-resistant melanoma, is unknown. Here, we found that molecular targeting of FASN in melanoma cells resistant to the BRAF inhibitor PLX4032 increased the sensitivity to the drug. Up-regulation of DHCR24 upon FASN targeting revealed the activation of druggable compensatory pathways sustaining the growth of resistant cells.Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.