NF1 alterations in cancers: therapeutic implications in precision medicine

ABSTRACTIntroduction NF1 is a tumor suppressor gene encoding neurofibromin, an inhibitor of the RAS/MAPK and PI3K-AKT-mTOR signaling pathways. NF1 germline pathogenic variants cause the tumor predisposition syndrome neurofibromatosis type 1. Targeted therapies (MEK inhibitors) have been approved for benign nerve sheath tumors in neurofibromatosis type 1 patients. NF1 somatic alterations are present in ~5% of all human sporadic cancers. In melanomas, acute myeloid leukemias and lung adenocarcinomas, the NF1 somatic alteration frequency is higher (~15%). However, to date, the therapeutic impact of NF1 somatic alterations is poorly investigated.Areas covered This review presents a comprehensive overview of targeted therapies and immunotherapies currently developed and evaluated in vitro and in vivo for NF1-altered cancer treatment. A PubMed database literature review was performed to select relevant original articles. Active clinical trials were researched in ClinicalTrials.gov database in August 2022. TCGA and HGMD® databases were consulted.Expert opinion This review highlights the need to better understand the molecular mechanisms of NF1-altered tumors and the development of innovative strategies to effectively target NF1-loss in human cancers. One of the current major challenges in cancer management is the targeting of tumor suppressor genes such as NF1 gene. Currently, most studies are focusing on inhibitors of the RAS/MAPK and PI3K-AKT-mTOR pathways and immunotherapiesI: inhibitor. Adapted from 'PI3K/Akt, RAS/MAPK, JAK/STAT signaling,' by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates.KEYWORDS: BiomarkerscancerimmunotherapiesNF1PI3K-AKT-MTOR signaling pathwayRAS/MAP kinase signaling pathwaytargeted therapies Article highlights Targeting loss-of-function mutations of tumor suppressor gene – like NF1 - is generally indirectThe use of MEK inhibitors has shown a significant improvement for neurofibromatosis type 1 patients with plexiform neurofibromasNF1 is not always part of the panel of genes routinely analyzed in cancer and few clinical data are found in the literature for NF1-mutated sporadic cancersCurrently, most studies are focusing on inhibitors of the RAS/MAPK and PI3K-AKT-mTOR pathways and immunotherapies.Clinical trials for sporadic cancers with somatic NF1 mutations are neededAbbreviations ABC-Bio=Advanced Breast Cancer BiopsyAML=Acute myeloid leukemiaATRA=All-trans retinoic acidCN=Cutaneous NeurofibromaCNV=Copy Number VariantsEMA=European Medicines AgencyEMT=Epithelial-Mesenchymal TransitionFDA=Food and Drug AdministrationHGMD®=Human Gene Mutation DatabaseLGG=Low Grade GliomaMAPK=Mitogen-Activated Protein KinaseMPNST=Malignant Peripheral Nerve Sheath TumorsNF1=Neurofibromatosis type 1NSLCL=Non-Small Cell Lung CancersONG=Optic Nerve GliomaOS=Overall SurvivalPN=Plexiform NeurofibromasPFS=Progression-Free SurvivalRAS/MAPK=Mitogen-Activated Protein KinaseTKI=tyrosine kinase inhibitorsTMB=Tumor Mutation BurdenDeclaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contributionsJ-S Giraud: Investigation, Formal Analysis, Writing – original draft preparation, Writing – review and editingI Bièche: Validation, Writing – review & editingE Pasmant: Resources, Supervision, Validation, Writing – review & editingC Tlemsani: Conceptualization, Project Administration, Supervision, Validation, Writing – review & editingSupplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2023.2263836Additional informationFundingThis paper was not funded.