Ricerc@Sapienza

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.