https://orcid.org/0000-0002-3342-1704
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ABSTRACT
Introduction
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 immunotherapies
GRAPHICAL ABSTRACT
Article highlights
Targeting loss-of-function mutations of tumor suppressor gene – like NF1 - is generally indirect
The use of MEK inhibitors has shown a significant improvement for neurofibromatosis type 1 patients with plexiform neurofibromas
NF1 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 cancers
Currently, 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 needed
Abbreviations
| ABC-Bio | = | Advanced Breast Cancer Biopsy |
| AML | = | Acute myeloid leukemia |
| ATRA | = | All-trans retinoic acid |
| CN | = | Cutaneous Neurofibroma |
| CNV | = | Copy Number Variants |
| EMA | = | European Medicines Agency |
| EMT | = | Epithelial-Mesenchymal Transition |
| FDA | = | Food and Drug Administration |
| HGMD® | = | Human Gene Mutation Database |
| LGG | = | Low Grade Glioma |
| MAPK | = | Mitogen-Activated Protein Kinase |
| MPNST | = | Malignant Peripheral Nerve Sheath Tumors |
| NF1 | = | Neurofibromatosis type 1 |
| NSLCL | = | Non-Small Cell Lung Cancers |
| ONG | = | Optic Nerve Glioma |
| OS | = | Overall Survival |
| PN | = | Plexiform Neurofibromas |
| PFS | = | Progression-Free Survival |
| RAS/MAPK | = | Mitogen-Activated Protein Kinase |
| TKI | = | tyrosine kinase inhibitors |
| TMB | = | Tumor Mutation Burden |
Declaration of interest
The 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 disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
J-S Giraud: Investigation, Formal Analysis, Writing – original draft preparation, Writing – review and editing
I Bièche: Validation, Writing – review & editing
E Pasmant: Resources, Supervision, Validation, Writing – review & editing
C Tlemsani: Conceptualization, Project Administration, Supervision, Validation, Writing – review & editing
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2023.2263836