Combination mTOR and SHP2 inhibitor treatment of lymphatic malformation endothelial cells

Area of Science:

• Oncology
• Vascular Biology
• Pharmacology

Background:

• Complex lymphatic malformations (LM) are often treated with mammalian target of rapamycin (mTOR) inhibitors like rapamycin, which targets the phosphoinositide 3-kinase (PI3K) pathway.
• Rapamycin treatment for LM can be lengthy, with variable efficacy and frequent relapses, suggesting underlying resistance mechanisms.
• Rat sarcoma virus (RAS) pathway abnormalities are implicated in LM and may contribute to rapamycin resistance.

Purpose of the Study:

• To investigate the efficacy of combining a SHP2 inhibitor with rapamycin for treating lymphatic malformations.
• To determine if dual inhibition of the PI3K and RAS pathways offers a synergistic therapeutic effect on LM cells.

Main Methods:

• Primary cells from surgically resected lymphatic malformations were used for in vitro studies.
• Cells were treated with rapamycin (mTOR/PI3K inhibitor) and SHP099 (SHP2 inhibitor).
• Assessed the impact of combination therapy on cell growth, migration, and lymphangiogenesis.

Main Results:

• Combination treatment with rapamycin and SHP099 resulted in a synergistic reduction in LM cell growth.
• The combined therapy significantly inhibited cell migration and lymphangiogenesis in vitro.
• SHP2 inhibition, upstream of the RAS pathway, enhanced the anti-proliferative effects of rapamycin.

Conclusions:

• Targeting both PI3K and RAS signaling pathways simultaneously may be a more effective strategy for treating lymphatic malformations.
• Combination therapy with rapamycin and SHP2 inhibitors demonstrates potential for improved LM treatment outcomes.
• This approach could overcome resistance mechanisms and reduce relapse rates in patients with head and neck LMs.