<i>NF1</i> alterations in cancers: therapeutic implications in precision medicine

<i>NF1</i> is a tumor suppressor gene encoding neurofibromin, an inhibitor of the RAS/MAPK and PI3K-AKT-mTOR signaling pathways. <i>NF1</i> 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. <i>NF1</i> somatic alterations are present in ~5% of all human sporadic cancers. In melanomas, acute myeloid leukemias and lung adenocarcinomas, the <i>NF1</i> somatic alteration frequency is higher (~15%). However, to date, the therapeutic impact of <i>NF1</i> somatic alterations is poorly investigated. This review presents a comprehensive overview of targeted therapies and immunotherapies currently developed and evaluated <i>in vitro</i> and <i>in vivo</i> for <i>NF1</i>-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. This review highlights the need to better understand the molecular mechanisms of <i>NF1</i>-altered tumors and the development of innovative strategies to effectively target <i>NF1</i>-loss in human cancers. One of the current major challenges in cancer management is the targeting of tumor suppressor genes such as <i>NF1</i> gene. Currently, most studies are focusing on inhibitors of the RAS/MAPK and PI3K-AKT-mTOR pathways and immunotherapies