NF1 and Neurofibromin: A Brake on RAS

Neurofibromin as a RAS-GAP

RAS proteins are active when bound to GTP and inactive when the GTP is hydrolysed to GDP. RAS hydrolyses GTP slowly on its own; GTPase-activating proteins (GAPs) speed this up by orders of magnitude.

Neurofibromin is one of the two main RAS-GAPs in most cells. When it is lost, RAS stays in its GTP-bound active state longer, raising signalling through RAF-MEK-ERK and, to a lesser extent, PI3K.

Neurofibromatosis Type 1

Germline loss-of-function NF1 variants cause neurofibromatosis type 1, with cafe-au-lait macules, cutaneous and plexiform neurofibromas, optic pathway gliomas, learning differences and an increased risk of malignant peripheral nerve sheath tumours and certain leukaemias.

As with other tumour-suppressor syndromes, tumours arise where the second NF1 allele is also lost.

NF1 Loss in Sporadic Cancer

Somatic NF1 inactivation is recurrent in melanoma (a distinct subtype from BRAF- and NRAS-mutant melanoma), glioblastoma, lung adenocarcinoma, ovarian cancer and others.

Because NF1 loss activates the same pathway as a RAS mutation, these tumours are often grouped with RAS-pathway-altered cancers for research purposes, though NF1 loss is harder to detect reliably.

Targeting the Consequence

There is no way to restore a lost tumour suppressor, so treatment targets the downstream pathway. The MEK inhibitor selumetinib is approved for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1.

In NF1-mutant cancers, MEK inhibition has shown activity in some settings but is generally less effective as a single agent than targeting an activating kinase mutation, and combinations are being explored.

Interpretation Notes

NF1 is a very large gene with many possible loss-of-function variants and pseudogenes, so calling true inactivation, especially copy loss and splice variants, requires a capable assay.

A somatic NF1 alteration in a tumour does not by itself indicate neurofibromatosis type 1; that is a germline diagnosis made clinically.

Key Takeaways

• ·Neurofibromin accelerates RAS GTP hydrolysis; losing it prolongs RAS activation.
• ·Germline NF1 loss causes neurofibromatosis type 1 with nerve-sheath tumours and gliomas.
• ·Somatic NF1 loss activates RAS-MAPK in melanoma, glioblastoma, lung and other cancers.
• ·MEK inhibition (selumetinib) treats plexiform neurofibromas; cancer activity is more variable.