Temporary Cell Cycle Arrest in Human Scalp Hair Follicles and Their Epithelial Stem Cells by ALRN-6924: A Novel Strategy to Selectively Protect p53-Wildtype Cells Against Paclitaxel-Induced Alopecia

The study investigates the use of ALRN-6924, a dual inhibitor of MDM2/MDMX, to protect human scalp hair follicles (HFs) from paclitaxel (PTX)-induced alopecia. ALRN-6924 activates p53, leading to upregulation of p21 and transient cell cycle arrest in p53-wild-type cells, sparing p53-mutant cancer cells. In organ-cultured human anagen scalp HFs, ALRN-6924 pretreatment significantly increased p21+ hair matrix (HM) and bulge stem cells (SCs), reduced melanin clumps, apoptosis, pathological mitosis, and DNA damage in PTX-treated HFs. It also mitigated PTX-induced pathological epithelial-mesenchymal transition in HF SCs without promoting catagen development. Thus, ALRN-6924 may prevent or reduce both acute and permanent chemotherapy-induced alopecia (CIA).