Year 2025 - Research project funded by Agorà
- 19 ore fa
- Tempo di lettura: 2 min
RESEARCHER AND PROJECT
Simone Lubrano
Born in Livorno in 1985
Degree in Biological and Molecular Sciences, University of Pisa
PhD in Molecular Medicine, University of Siena
Project location Scuola Normale Superiore, Pisa
Project objective
To identify the molecular mechanisms underlying acquired resistance to targeted therapies in melanoma, with a particular focus on the interaction between the RAF/MEK and FAK signaling pathways, in order to develop pharmacological combination strategies capable of overcoming such resistance and improving the durability of therapeutic response.
PRESENTATION OF THE FUNDED PROJECT
In 2025, the research project supported by Agorà in collaboration with Fondazione Umberto Veronesi continues, under the guidance of Dr. Simone Lubrano, focused on the study of resistance mechanisms in cutaneous melanoma and the identification of new therapeutic strategies based on the combined inhibition of the RAF/MEK and FAK signaling pathways. The main objective of the study is to understand how melanoma cells develop resistance to targeted and immunotherapies, and to identify pharmacological combinations capable of overcoming such resistance, prolonging clinical response in patients.
Molecular analysis of resistance
During the research, a panel of melanoma cell lines resistant to the RAF/MEKi + FAKi combination has been generated from the A375 cell line. Preliminary cell viability assays and immunoblotting studies confirmed acquired resistance to treatment.
These models will undergo bulk RNA sequencing (RNA-seq) to identify the transcriptional alterations characterizing resistant cells compared to drug-sensitive ones. Data will be analyzed using advanced bioinformatic tools, including Gene Set Enrichment Analysis (GSEA) and gene regulatory network reconstruction, to identify recurrent signaling nodes underlying resistance.
Validation of new therapeutic strategies
In parallel, candidate genes and pathways emerging from transcriptomic analysis will be validated in vitro through pharmacological co-targeting experiments, siRNA-mediated gene knockdown, and cell viability assays. Synergistic drug interactions will be quantified using established statistical models such as Loewe and ZIP.
To strengthen the clinical relevance of the findings, resistance-associated transcriptional signatures will be cross-referenced with publicly available patient datasets (CCLE, TCGA, CPTAC, ICGC), with the aim of defining biomarker-informed patient stratification strategies.
Future perspectives
The expected results represent a concrete step toward more effective management of advanced melanoma, particularly for patients who do not respond to currently available therapies. The identification of novel pharmacological combinations and predictive biomarkers may contribute to improving the design of a forthcoming clinical trial with avutometinib + FAKi, increasing the likelihood of durable responses and opening new therapeutic perspectives for other MAPK-driven cancers.