Despite the advent of molecular targeted agents and immune checkpoint inhibitors successfully revolutionized the treatment of patients with advanced melanoma, therapeutic response in patients with metastatic melanoma tend to be short-lived because of the acquisition of drug resistance through functional or mutational reactivation of the MAPK pathway.
It has been reported the existence of an uncommon subpopulation of tumor cells with distinctive features, often defined as cancer stem cells (CSCs) probably responsible for cancer relapse.
Our group has previously reported that lipid metabolism is linked to CSCs initiation and maintenance demonstrating that SCD1, involved in generation of monounsaturated fatty acids (MUFAs), is a key factor for lung cancer-initiating cells, and that its inhibition selectively kills CSCs. We observed that the treatment with MAPKi results in the enrichment of a slow-cycling subpopulation characterized by an overexpression of JARID1B, that identifies melanoma CSCs, and by an high content of MUFA. I also demonstrated that the abrogation of SCD1 activity in combination of MAPKi overcame the intrinsic resistance of spheroids to BRAF and MEK inhibitors.
Other authors demonstrated that treatment of JARID1Bhigh slow-cycling melanoma cells with vemurafenib resulted in metabolic reprogramming through induction of OxPhos and in increased resistance to MAPKi.
The project presented here will be focused on the study of the interplay between lipid metabolism and mitochondrial function in the development of resistance to target therapies to propose new strategies for BRAF-mutated melanoma aimed at decreasing disease relapse after MAPKi and prolonging patients¿ survival.
I will evaluate SCD1 as predictive marker and the metabolic signature of sensitive or resistance cells to identify clinical biomarkers able to predict response to MAPKi.
Despite the advances in the early diagnosis and the generation of new targeted therapies, melanoma is still the leading cause of cancer related mortality worldwide. Most of the treatment failure is caused by the onset of resistance to chemotherapies and the limited efficacy of the targeted therapies now available. Many evidences demonstrated the existence of cancer stem initiating cells inside tumors. This population of cells, which shows stem cell traits, results resistant to conventional chemotherapies and likely responsible of tumor relapse. Therefore, lipid metabolism will be studied to identify new molecular mechanisms involved in the progression of melanoma, in order to identify innovative strategies based on the combined administration of BRAF / MEK / SCD1 inhibitors.In conclusion we will to reveal the interplay between lipid metabolism and mitochondrial function in the determination of metabolic reprogramming to develop new strategies for BRAF-mutated melanoma based on targeting of CSCs. This may be a promising strategy for overcoming the resistance to MAPKi. The discovery of a metabolic signature of sensitive and resistance cells may be useful to identify clinical biomarkers to stratify BRAF-mutated melanoma into sensitive and resistant subgroup.