Unveiling the Molecular Mechanisms of Neurofibromin-1 Regulation for Therapeutic Targeting in Neurofibromatosis Type 1
Abstract
Background: Neurofibromatosis type 1 is one of the most common dominantly inherited genetic diseases. Patients with this disease frequently suffer from learning disabilities, bone deformities, and benign tumors. These benign tumors often cause pain and disfiguration and sometimes develop into fatal, incurable, malignant cancers such as malignant peripheral nerve sheath tumors (MPNSTs). Neurofibromatosis type 1 is caused by mutations in the NF1 gene that mean it encodes a faulty NF1 protein that cannot perform its essential functions within cells. To understand why losing these functions causes the symptoms of neurofibromatosis type 1 and to develop treatments, scientists must first understand how the normal NF1 protein functions and how other proteins in the cell control NF1. However, how NF1 s functions are controlled is not understood, and this is stunting progress. What we do know is that NF1 is vital for switching off the activity of a very important protein called RAS. RAS is a master controller of many processes within cells, including telling cells to grow and divide. RAS is activated by hormone signals from outside cells, and in healthy cells, RAS activity is short-lived due to strict controls imposed by other proteins. NF1 is one of the most important proteins to impose these strict controls to ensure RAS is only active briefly when appropriate. If RAS is active for too long, then this causes problems, including triggering cells to divide and grow too much, ultimately causing tumors and cancer. One of the proteins that active RAS signals to and activates to tell cells to divide is called ERK. ERK initiates and coordinates cell growth and division. Mutations of NF1 in neurofibromatosis type 1 patients therefore cause inappropriate prolonged activation of RAS and, consequently, ERK. Over time, this chronic activation of ERK causes neurofibromatosis type 1 disease, including tumor development. However, in normal healthy cells, no one fully understands when and how NF1 switches off RAS. Improving our knowledge of these molecular mechanisms is critical to develop and optimize effective treatments for neurofibromatosis type 1. Rationale and Objectives: Our laboratory has now made a potentially crucial breakthrough in our molecular understanding of NF1. We have strong evidence that ERK feeds back to control NF1, and this is likely a key missing link in our understanding of NF1. We think, like a rheostat, ERK negatively feeds back to itself by activating NF1, thereby turning off RAS and further ERK activation. This negative feedback rheostat would be lost when NF1 is mutated, meaning ERK no longer switches off RAS and itself as normal. Prolonged inappropriate ERK activity may then drive tumor formation and the symptoms of neurofibromatosis type 1. I want to understand how ERK is controlling NF1 and whether loss of this control is what drives neurofibromatosis type 1 disease progression. Clinical Implications: We think this study will be of immediate benefit to patients with plexiform neurofibromas (pNFs) undergoing MEK inhibitor (MEKi) therapy. RAS activates ERK via the MEK protein. Inhibiting MEK prevents the RAS activation of ERK that causes neurofibromas, which is why MEKi have been successful for patients recently. Our proposed mechanism, described above, could explain why MEKi are effective against NF1-mutant pNFs, but perform less well for sporadic cancers with other mutations in the RAS pathway. Experience shows that optimal MEKi therapy requires knowledge of how NF1, RAS, and ERK interact and dynamically signal. Thus, our work may help clinicians enhance the benefits of MEKi further, including neurofibroma regressions and management of pain. In addition, distinct MEKi, such as selumetinib and trametinib, have different properties and disrupt the signals from RAS to ERK by inhibiting MEK in subtly different ways. No one knows which of these classes of MEKi will be most effective o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110502
Entities
People
- Matthew Sale
Organizations
- United States Army
- University of California, San Francisco