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.