Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation.

Emerging evidence indicates that non-mutational drug tolerance mechanisms underlie the survival of residual cancer "persister" cells. Here, we find that BRAF(V600E) mutant melanoma persister cells tolerant to BRAF/MEK inhibitors switch their metabolism from glycolysis to oxidative respiration supported by peroxisomal fatty acid ß-oxidation (FAO) that is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARα). Knockdown of the key peroxisomal FAO enzyme, acyl-CoA oxidase 1 (ACOX1), as well as treatment with the peroxisomal FAO inhibitor thioridazine, specifically suppresses the oxidative respiration of persister cells and significantly decreases their emergence. Consistently, a combination treatment of BRAF/MEK inhibitors with thioridazine in human-melanoma-bearing mice results in a durable anti-tumor response. In BRAF(V600E) melanoma samples from patients treated with BRAF/MEK inhibitors, higher baseline expression of FAO-related genes and PPARα correlates with patients' outcomes. These results pave the way for a metabolic strategy to overcome drug resistance.

Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma.

Preventing the immune escape of tumor cells by blocking inhibitory checkpoints, such as the interaction between programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) receptor, is a powerful anticancer approach. However, many patients do not respond to checkpoint blockade. Tumor PD-L1 expression is a potential efficacy biomarker, but the complex mechanisms underlying its regulation are not completely understood. Here, we show that the eukaryotic translation initiation complex, eIF4F, which binds the 5' cap of mRNAs, regulates the surface expression of interferon-γ-induced PD-L1 on cancer cells by regulating translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor. eIF4F complex formation correlates with response to immunotherapy in human melanoma. Pharmacological inhibition of eIF4A, the RNA helicase component of eIF4F, elicits powerful antitumor immune-mediated effects via PD-L1 downregulation. Thus, eIF4A inhibitors, in development as anticancer drugs, may also act as cancer immunotherapies.

[Not Available]. / Place des anti-PD1 dans la prise en charge des mélanomes cutanés.

ANTI-PD1 ROLE IN TREATMENT OF CUTANEOUS MELANOMA: The treatment of metastatic melanoma dramatically changed over the last years. Two therapeutic revolutions emerged in parallel, targeted anti-BRAF and anti-MEK therapies, for patients BRAFV600 mutated and immunotherapy with immune checkpoint blockers using anti-CTLA-4 then anti-PD1 monoclonal antibodies. Indeed, melanoma immunotherapy was a golden objective for many years but in spite of important efforts using cytokines (interferon, interleukin) and different vaccine approaches no objective improvement of patients 'prognosis was obtained. Ipilimumab, authorized in 2011, was the first drug which showed a benefit of overall survival in patients with metastatic melanoma in spite a low response rate (10-15) and the occurrence of about 25% of serious toxicity. Anti-PD1 appear as a new generation of immune checkpoint blockade with response rates between 30 to 40% of the patients, a proven overall survival benefit as compared with chemotherapy or ipilimumab and less toxicity than ipilimumab. Two molecules, pembrolizumab and nivolumab were recently approved in monotherapy, for metastatic melanoma. Several questions remain unresolved: the respective indications of anti-PD1 and targeted therapies in first line therapy in patients with BRAF mutant melanoma, the benefit of combining immunotherapy with radiotherapy or with targeted therapies, the optimal treatment duration, and the benefit of the anti-PD1 in the adjuvant setting. The combination of ipilimumab and nivolumab, recently approved by the FDA but not yet in Europ, shows an improvement of the objective response rates (50-57%) and progression free survival compared with nivolumab but is associated with an higer incidence of serious adverse events (more than 50%).

Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.

Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.