Eleonora Leucci, Speaker at Cosmetology Conferences 2022
LKI Leuven Cancer Institute, Belgium
Title : Lncrnas and beyond: uncoupling cytosolic and mitochondrial-translation as an effective anti-melanoma strategy


The ability of tumour cells to adapt to environmental stress, including therapeutic insult, contributes to tumour evolution and drug resistance. Drug-tolerant persister (DTP) cells from multiple cancer types often exhibit elevated activation of the integrated stress response (ISR), which promotes survival by dampening CAP-dependent mRNA translation, one of the most energy-demanding cellular processes. Here we show that activation of ISR in DTP cells promotes selective translation of a subset of mRNAs encoding for mitochondrial proteins in melanoma. Moreover, DTP survival upon therapeutic pressure relies on the ISR-dependent concomitant upregulation of mitochondrial protein synthesis, a vulnerability that can be exploited by knocking down the melanoma-specific lncRNA SAMMSON or by using FDA-approved mitoribosome-targeting antibiotics. Accordingly, such agents sensitize to MAPK inhibition, thereby delaying –and even preventing– the development of resistance in BRAFV600E PDX models. Additionally, this treatment hampers the growth of therapy-resistant and NRAS-mutant cutaneous melanomas as well as uveal melanomas and prevents resistance to both immunotherapy and targeted therapy. Consistently, a melanoma patient exposed to doxycycline, a mitoribosome-targeting antibiotic commonly used to treat infections, experienced a complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF-mutant melanoma, and a therapeutic option for the treatment of NRAS-driven and immunotherapy-resistant cutaneous and uveal melanomas that can be easily implemented in the clinic.


Trace, Department of Oncology, LKI Leuven Cancer Institute, KULeuven, Leuven, Belgium.

Laboratory for RNA Cancer Biology, Department of Oncology, LKI Leuven Cancer Institute, KULeuven, Leuven, Belgium