Luca Falzone, MSc, Ph.D
University of Catania, Catania, Italy
Prognostic role of both BRAF/ERK and PI3K/AKT pathway alterations in cutaneous melanoma
Authors: Luca Falzone, Massimo Libra
Melanoma is one of the leading cause of death because of skin cancers. Although several therapeutic strategies have been developed during the years, a significant fraction of melanoma patients often experiences therapeutic failure due to the arising of drug-resistance mechanisms. Therefore, the identification of new biomarkers of therapeutic response is one of the main challenges in melanoma care.
In the present study, the circulating-free DNA BRAFV600E and PIK3CAH1047R were proposed as marker of therapeutic response in melanoma patients. Beside these two circulating mutations, also the serum levels of Matrix Metalloproteinase-9 (MMP-9) were analysed in melanoma samples and correlated to both the presence of BRAF circulating mutation and the therapeutic efficacy.
Furthermore, in order to shed light on the mechanisms behind the onset of drug resistance, several in vitro studies were performed by inducing mutation on PIK3CA gene in A375 melanoma cells.
Moreover, different combinations of drugs were tested in PIK3CAH1047R mutated melanoma cells to determine the best therapeutic approach able to overcome drug resistance.
The evaluation of the circulating levels of BRAFV600E mutation and MMP-9 revealed that only the 42% of melanoma patients was positive to the circulating-free DNA BRAFV600E mutation and that higher levels of MMP-9 were associated with poor PFS and OS in patients with circulating-free DNA BRAFV600E mutation. Unexpectedly, regarding the PIK3CAH1047R mutation it was observed a higher percentage (>80%) of positive patients.
Finally, the over-expression of PIK3CAH1047R mutation induced in A375 cells was correlated to Dabrafenib resistance while the combined therapy with BRAF and PI3K inhibitors was able to overcome the previously observed drug resistance.
Overall, these findings suggest that MMP-9 may represent a promising indicator of response to BRAF inhibitors in combination with the detection of BRAFV600E mutation and that the administration of both BRAF and PI3K inhibitors may represent a good therapeutic approach able to overcome drug resistance.
Luca Falzone is a PhD student within the PhD Program in Basic & Applied Biomedical Sciences at the University of Catania (Catania, Italy). He received the MSc in Medical Biotechnologies with full marks at the University of Catania in 2018. At the same University, he obtained the Bachelor Degree in Biomedical Laboratory Techniques in 2014. His research activity is focused on the molecular mechanisms of tumor development and progression with particular reference to the study of cancer cells and tumor microenvironment interactions, the study of the activation of the NGA/MMP-9, and the functional role of the hyper-activation of the RAF-MAPK-ERK and PI3K-AKT signal transduction pathways. The study of these mechanisms may allow to identify new markers that can be used for new diagnosis and therapeutic strategies. Furthermore, he is developing computational biology skills to be used for the identification of DNA methylation hotspots and microRNAs associated with tumor development.