Daytime SHP2 inhibitor dosing, when immune cell numbers are elevated, shrinks neurofibromas

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Neurofibromatosis type 1 (NF1) causes plexiform neurofibromas (PNFs) via RAS-MAPK pathway activation.
• MEK inhibitors reduce PNF size and tumor-associated myeloid cells.

Purpose of the Study:

• To investigate SHP2 inhibition's effects on PNF volume and immune microenvironment.
• To explore SHP2 inhibition's immunomodulatory potential and timing-dependent efficacy.

Main Methods:

• Utilized flow cytometry and single-cell RNA sequencing in a mouse model.
• Assessed tumor volume and immune cell populations following SHP2 inhibition.

Main Results:

• Both cobimetinib and SHP2 inhibitor RMC-4550 reduced PNF volume.
• CD163-negative macrophage abundance correlated with tumor size.
• SHP2 inhibition's efficacy was dependent on administration timing (daytime) and reversed by anti-PD1 therapy.

Conclusions:

• SHP2 inhibition offers a potential therapeutic strategy for PNFs.
• Targeting monocyte-derived macrophages and optimizing drug administration timing are key for effective SHP2 inhibitor therapy.