Immune Checkpoint Inhibitors and RAS–ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma

Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS-ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients.Funding: PC lab is supported by grant PID2021-126288OB-I00 from the Spanish Ministry of Science (MICIU/AEI/FEDER, UE); PIE 202220E003 from Agencia Estatal Consejo Superior de Investigaciones Científicas; and CIBERONC from the Instituto de Salud Carlos III (ISCIII). AP: Spanish Ministry of Science (PID2020-115605RB-I00), CIBERONC, Junta de Castilla y León (CSI146P20), and the CRIS Cancer Foundation. Our labs receive support from the European Union Regional Development Funding Program (FEDER)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Especifidad espacio temporal de las señales Ras-ERK en la determinación de respuestas biológicas

La cascada de señalización de ERK(Extracellular-Signal-Regulated Kinase) es una ruta formada por proteínas quinasas activadas por mitógenos (MAPKs) que regula una amplia variedad de procesos celulares, tan diferentes como la proliferación, diferenciación, supervivencia y el estrés. La activación de la ruta Ras-ERK se ha descrito, predominantemente, desde la membrana plasmática, pero en la última década se ha demostrado que Ras también puede ser activada en otras sublocalizaciones celulares, como por ejemplo en retículo endoplasmático, mitocondria o aparato de Golgi. En este trabajo se demuestra que la localización subcelular de Ras dentro de la célula es determinante en la capacidad de rescate de viabilidad celular en células carentes de Ras endógeno. Por otra parte, se sabe que la duración de la actividad de ERK puede ser determinante en la determinación de respuestas biológicas. En células MCF7 se producen diferentes respuestas en función del estímulo, asociadas con distinta cinética de activación, quedando demostrado que las variaciones temporales de la señal Ras-ERK son responsables de la determinación de una respuesta biológica

Characterisation of a nucleo-adhesome

In addition to central functions in cell adhesion signalling, integrin-associated proteins have wider roles at sites distal to adhesion receptors. In experimentally defined adhesomes, we noticed that there is clear enrichment of proteins that localise to the nucleus, and conversely, we now report that nuclear proteomes contain a class of adhesome components that localise to the nucleus. We here define a nucleo-adhesome, providing experimental evidence for a remarkable scale of nuclear localisation of adhesion proteins, establishing a framework for interrogating nuclear adhesion protein functions. Adding to nuclear FAK’s known roles in regulating transcription, we now show that nuclear FAK regulates expression of many adhesion-related proteins that localise to the nucleus and that nuclear FAK binds to the adhesome component and nuclear protein Hic-5. FAK and Hic-5 work together in the nucleus, co-regulating a subset of genes transcriptionally. We demonstrate the principle that there are subcomplexes of nuclear adhesion proteins that cooperate to control transcription.The work was funded by Cancer Research UK (grants C157/A15703 and C157/A24837 to M.C.F.) and supported by the Wellcome Trust (multiuser equipment grant 208402/Z/17/Z to A.v.K.)