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.

Sequencing-based transcriptomics has significantly redefined the concept of genome complexity, leading to the identification of thousands of lncRNA genes identification of thousands of lncRNA genes whose products possess transcriptional and/or post-transcriptional regulatory functions that help to shape cell functionality and fate. Indeed, it is well-established now that lncRNAs play a key role in the regulation of gene expression through epigenetic and posttranscriptional mechanims. The rapid increase of studies reporting lncRNAs alteration in cancers has also highlighted their relevance for tumorigenesis. Herein we describe the most prominent examples of well-established lncRNAs having oncogenic and/or tumor suppressive activity. We also discuss how technical advances have provided new therapeutic strategies based on their targeting, and also report the challenges towards their use in the clinical settings.

Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, resistance mechanisms limit its clinical benefit. Here we characterise LISRR , a cancer-specific lncRNA highly expressed in melanoma patients refractory to ICB. In cells undergoing (therapeutic) stress, LISRR recruits DAZAP1 (Deleted in AZoospermia Associated Protein 1) to polysomes and drives the assembly of a subset of ribosomes at the endoplasmic reticulum, directing the synthesis of an immunosuppressive translatome. This includes the immune checkpoint PD-L1 and the enzymes necessary for building the glycocalyx, the sugar coat surrounding the cells. Notably, proper glycocalyx assembly is required for spermatozoa immune evasion during fertilization. Accordingly, targeting LISRR activates immune responses and re-sensitizes to ICB in co-culture models, ex vivo in patient explants, and in vivo in humanized patient-derived models. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based cancer-specific strategy to overcome intrinsic resistance to ICB.

KRAS^G12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS oncogenic signaling is responsible for modulation of tumor microenvironment, with translation factors being among the most prominent deregulated targets. In the present study, we used TALENs to edit EGFR^WT CL1-5 and A549 cells for integration of a Tet-inducible KRAS^G12C expression system. Subsequent analysis of both cell lines showed that cap-dependent translation was impaired in CL1-5 cells via involvement of mTORC2 and NF-κB. In contrast, in A549 cells, which additionally harbor the KRAS^G12S mutation, cap-dependent translation was favored via recruitment of mTORC1, c-MYC and the positive regulation of eIF4F complex. Downregulation of eIF1, eIF5 and eIF5B in the same cell line suggested a stringency loss of start codon selection during scanning of mRNAs. Puromycin staining and polysome profile analysis validated the enhanced translation rates in A549 cells and the impaired cap-dependent translation in CL1-5 cells. Interestingly, elevated translation rates were restored in CL1-5 cells after prolonged induction of KRAS^G12C through an mTORC1/p70S6K-independent way. Collectively, our results suggest that KRAS^G12C signaling differentially affects the regulation of the translational machinery. These differences could provide additional insights and facilitate current efforts to effectively target KRAS.

Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxidative phosphorylation. LENOX expression was upregulated following treatment with MAPK inhibitors, facilitating a metabolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, combined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression.Significance:The lncRNA LENOX is a novel regulator of melanoma metabolism, which can be targeted in conjunction with MAPK inhibitors to eradicate melanoma cells.

LENOX overexpression promotes resistance to BRAF and glycolysis inhibition.