Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma.

The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAFV600E melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced 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 NRAS-driven and immunotherapy-resistant tumors.

SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation.

Synchronization of mitochondrial and cytoplasmic translation rates is critical for the maintenance of cellular fitness, with cancer cells being especially vulnerable to translational uncoupling. Although alterations of cytosolic protein synthesis are common in human cancer, compensating mechanisms in mitochondrial translation remain elusive. Here we show that the malignant long non-coding RNA (lncRNA) SAMMSON promotes a balanced increase in ribosomal RNA (rRNA) maturation and protein synthesis in the cytosol and mitochondria by modulating the localization of CARF, an RNA-binding protein that sequesters the exo-ribonuclease XRN2 in the nucleoplasm, which under normal circumstances limits nucleolar rRNA maturation. SAMMSON interferes with XRN2 binding to CARF in the nucleus by favoring the formation of an aberrant cytoplasmic RNA-protein complex containing CARF and p32, a mitochondrial protein required for the processing of the mitochondrial rRNAs. These data highlight how a single oncogenic lncRNA can simultaneously modulate RNA-protein complex formation in two distinct cellular compartments to promote cell growth.

Control of nucleolar stress and translational reprogramming by lncRNAs.

Under adverse environmental conditions, cells activate stress re-sponses that favour adaptation or, in case of irreversible damage, induce cell death. Multiple stress response pathways converge to downregulate ribo-some biogenesis and translation since these are the most energy consuming processes in the cell. This adaptive response allows preserving genomic stabil-ity and saving energy for the recovery. It follows that the nucleolus is a major sensor and integrator of stress responses that are then transmitted to the translation machinery through an intricate series of conserved events. Long non-coding RNAs (lncRNAs) are emerging as important regulators of stress-induced cascades, for their ability to mediate post-transcriptional responses. Consistently, many of them are specifically expressed under stress conditions and a few have been already functionally linked to these processes, thus fur-ther supporting a role in stress management. In this review we survey differ-ent archetypes of lncRNAs specifically implicated in the regulation of nucleo-lar functions and translation reprogramming during stress responses.