Progetto AIRC MFAG 23453 (DSB.AD001.159)
Project areaOncologia e Immunologia (DSB.AD001)
Structure responsible for the research project
Primary therapeutic options for advanced or metastatic BRAFV600E-mutated papillary and anaplastic thyroid carcinomas (PTC and ATC) are B-raf inhibitors. However, patients acquire resistance because tumor cells use alternative routes to activate MAPK pathway bypassing B-raf inhibition. Recent reports, including ours, reveal that BRAF mutations drive differential pathways activation compared to RAS ones. Exploring long non-coding RNAs induced by specific oncogenic alterations we identified COMET as natural antisense of MET oncogene, over-expressed in BRAF-like tumors and induced downstream MAPK pathway by B-raf. COMET is part of a co-expression network and its knockdown down-regulates different MAPK-related oncogenes, including MET and ERBB3. Strikingly, COMET depletion inhibits viability, proliferation, colony forming ability, cell motility and invasiveness of BRAF-like tumor cells and, more interestingly, markedly increases tumor cells' sensitivity to vemurafenib.
We aim testing the hypothesis of adopting COMET silencing in vivo as new therapeutic option in advanced and drug resistant BRAF-mutated PTCs and ATCs.(Several evidences strongly indicate [...]
We expect to:(- identify COMET-interacting partners and COMET-regulated gene network;(- provide mechanistic proof of COMET activity;(- propose the combination of COMET silencing and B-raf inhibition as new therapeutic approach in advanced and drug-resistant BRAF-mutant PTCs and ATCs.
Targeting COMET rather than hyper-activated oncogenes (e.g. MET, ERK etc) - having high and ubiquitous expression and relevant functions in healthy cells - will enhance sensitivity and specificity of therapies. In the spirit of precision oncology, combining COMET silencing to current therapies will provide clinicians new tools for personalized therapy in a specific tumor subtype, increasing patients' survival.
Start date of activity
Response and/or resistance to therapy, Thyroid carcinoma, BRAF/RAF kinases
Last update: 09/12/2023