The NF1 gene revisited - from bench to bedside

Abstract

Neurofibromatosis type 1 (NF1) is a relatively common tumour predisposition syndrome related to germline aberrations of NF1, a tumour suppressor gene. The gene product neurofibromin is a negative regulator of the Ras cellular proliferation pathway, and also exerts tumour suppression via other mechanisms. Recent next-generation sequencing projects have revealed somatic NF1 aberrations in various sporadic tumours. NF1 plays a critical role in a wide range of tumours. NF1 alterations appear to be associated with resistance to therapy and adverse outcomes in several tumour types. Identification of a patient's germline or somatic NF1 aberrations can be challenging, as NF1 is one of the largest human genes, with a myriad of possible mutations. Epigenetic factors may also also contribute to inadequate levels of neurofibromin in cancer cells. Clinical trials of NF1-based therapeutic approaches are currently limited. Preclinical studies on neurofibromin-deficient malignancies have mainly been on malignant peripheral nerve sheath tumour cell lines or xenografts derived from NF1 patients. However, the emerging recognition of the role of NF1 in sporadic cancers may lead to the development of NF1-based treatments for other tumour types. Improved understanding of the implications of NF1 aberrations is critical for the development of novel therapeutic strategies.

Figure 1. The role of NF1 and neurofibromin in the Ras pathway

G-protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), when activated by ligand, promote guanine nucleotide exchange to form activated Ras-GTP complex. Neurofibromin inactivates Ras by accelerating the conversion of active Ras-GTP to inactive GDP-bound Ras with its Ras-GTPase activity. Consequently, neurofibromin suppresses activation of the downstream effectors of Ras, including PI3K, Akt, mTOR, S6 kinase and RAF, MEK, ERK as well as RAC1 and PAK1. RTKs=receptor tyrosine kinases. Grb2=growth factor receptor bound 2. SOS=mammalian homolog of the Drosophila son of sevenless. RAS=rat sarcoma viral oncogene homologue. GDP=guanosine diphosphate. GTP=guanosine triphosphate. RAF=murine sarcoma viral oncogene homologue. MEK=MAPK-ERK kinase. PI3K=phosphatidylinositol-3–kinase. AKT=V-akt murine thymoma viral oncogene homologue 1. mTOR=mammalian target of rapamycin. Rac1=Ras-related C3 botulinum toxin substrate 1. PAK1=P21-Activated Kinase.

Figure 2. Frequency of NF1 mutation and homozygous deletion in human neoplasms (Source: The cBio Cancer genomics Portal; http://www.cbioportal.org)

Figure 3. Potential therapeutic strategies for NF1-deficient malignancies

The molecular therapies above have been tested in the preclinical setting, largely for MPNSTs. There is also data on some of the inhibitors for neurofibromin-deficient breast cancer, glioblastoma, AML, soft tissue sarcoma, lung cancer and melanoma. Combination therapy targeting more than one checkpoint may be required for optimal inhibition.