XMU-MP-1 Induces Growth Arrest in a Model Human Mini-Organ and Antagonizes Cell Cycle-Dependent Paclitaxel Cytotoxicity

In the study, XMU-MP-1, an inhibitor of the Hippo pathway kinases MST1/2, was tested for its ability to activate YAP1 in a model human mini-organ, specifically the hair follicle, to assess its potential in treating hair loss disorders. Contrary to expectations, XMU-MP-1 did not increase active YAP1 levels in the hair follicle. Instead, it unexpectedly reduced the proliferation of hair matrix keratinocytes, as indicated by a decrease in Ki-67+, EdU+, and phospho histone H3+ cells, and also counteracted the cytotoxic effects of the chemotherapy drug paclitaxel. The study concluded that XMU-MP-1 disrupts cell cycle progression in the hair follicle, potentially due to off-target effects, as it is known to inhibit 21 additional kinases besides MST1/2. The findings suggest that caution should be used when interpreting the effects of XMU-MP-1, particularly in tissues with actively proliferating cells.