TY - JOUR
T1 - Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma
AU - Fattore, Luigi
AU - Ruggiero, Ciro Francesco
AU - Pisanu, Maria Elena
AU - Liguoro, Domenico
AU - Cerri, Andrea
AU - Costantini, Susan
AU - Capone, Francesca
AU - Acunzo, Mario
AU - Romano, Giulia
AU - Nigita, Giovanni
AU - Mallardo, Domenico
AU - Ragone, Concetta
AU - Carriero, Maria Vincenza
AU - Budillon, Alfredo
AU - Botti, Gerardo
AU - Ascierto, Paolo Antonio
AU - Mancini, Rita
AU - Ciliberto, Gennaro
PY - 2019/7
Y1 - 2019/7
N2 - Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma. Although this issue has been mitigated by the development of combination therapies with BRAF plus MEK inhibitors, drug resistance inevitably occurs with time and results in clinical recurrences and untreatable disease. Hence, there is strong need of developing new combination therapies and non-invasive diagnostics for the early identification of drug-resistant patients. We report here that the development of drug resistance to BRAFi is dominated by a dynamic deregulation of a large population of miRNAs, leading to the alteration of cell intrinsic proliferation and survival pathways, as well as of proinflammatory and proangiogenic cues, where a prominent role is played by the miR-199b-5p/VEGF axis. Significant alterations of miRNA expression levels are detectable in tumor biopsies and plasma from patients after disease recurrence. Targeting these alterations blunts the development of drug resistance.
AB - Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma. Although this issue has been mitigated by the development of combination therapies with BRAF plus MEK inhibitors, drug resistance inevitably occurs with time and results in clinical recurrences and untreatable disease. Hence, there is strong need of developing new combination therapies and non-invasive diagnostics for the early identification of drug-resistant patients. We report here that the development of drug resistance to BRAFi is dominated by a dynamic deregulation of a large population of miRNAs, leading to the alteration of cell intrinsic proliferation and survival pathways, as well as of proinflammatory and proangiogenic cues, where a prominent role is played by the miR-199b-5p/VEGF axis. Significant alterations of miRNA expression levels are detectable in tumor biopsies and plasma from patients after disease recurrence. Targeting these alterations blunts the development of drug resistance.
U2 - 10.1038/s41418-018-0205-5
DO - 10.1038/s41418-018-0205-5
M3 - Article
C2 - 30254376
VL - 26
SP - 1267
EP - 1282
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 7
ER -