LB1018 ALRN-6924, a dual inhibitor of MDMX and MDM2, protects human scalp hair follicles and their epithelial stem cells from paclitaxel-induced toxicity

Abstract

Taxanes like paclitaxel (PTX) cause severe and often permanent chemotherapy-induced alopecia (CIA). We have previously shown that PTX damages human scalp hair follicles (HFs) by inducing massive mitotic defects and apoptosis in hair matrix (HM) keratinocytes as well as bulge stem cell DNA damage, and that pharmacological induction of transient G1 arrest can be HF- and stem cell-protective. We tested whether ALRN-6924 can protect human HFs from PTX-induced toxicity ex vivo. ALRN-6924 is a clinical-stage MDM2/MDMX dual inhibitor that activates p53 to upregulate p21, transiently arresting and selectively protecting healthy normal cells from chemotherapy in patients with p53-mutant cancers without protecting cancer cells.