Repurposing MEK Inhibitors for Lymphatic Malformations
Abstract
Sporadic lymphatic malformations (LMs) are chronic, progressive and debilitating diseases caused by errors in the development of the lymphatic vasculature. These diseases include generalized lymphatic anomaly, kaposiform lymphangiomatosis, Gorham-Stout disease, and central conducting lymphatic anomaly. LMs can result in life-threatening complications and the 5-year survival rate is as low as 51% for certain LMs. Several different treatments are used to manage the symptoms of LM patients and in recent years sirolimus (FDA-approved mTOR inhibitor) has become the standard of care for patients. However, not all patients respond to sirolimus. Therefore, there is an urgent need for new pharmacotherapies for sporadic LMs. We and others have recently identified somatic activating mutations in KRAS in LM patients. KRAS is a small G-protein that activates the RAF/MEK/ERK signaling pathway and the mechanism by which it causes lymphatic dysplasia is poorly understood. We have found that mice that express an active form of KRAS in their lymphatics (iLECKras mice)develop fewer lymphatic valves than control mice. We have also found that hyperactive KRAS signaling in lymphatics affects the localization of VE-Cadherin, a protein that is required for fluid shear stress signaling and lymphatic valve development and maintenance. The objectives of this application are to determine the mechanisms by which excessive KRAS signaling impairs lymphatic function and to test the ability of an FDA-approved MEK inhibitor to reverse lymphatic defects in our clinically relevant mouse model. Hyperactive KRAS signaling causes the disintegration of lymphatic valves by inhibiting VEcadherin signaling and that this can be reversed with trametinib.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1212486
Entities
People
- Michael Jr Dellinger
Organizations
- University of Texas at Dallas