CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Kayumba Ng'andu
  • Lars Brunken
  • Eleanor Lech
  • Ellen Mitchell
  • Nashat Hassan
  • Aaron O'Brien
  • Jennifer Jackson
  • Asim Shahmalak

Abstract

Taxanes are a leading cause of severe and permanent chemotherapy-induced alopecia. As the underlying pathobiology of taxane chemotherapy-induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell-rich outer root sheath compartments, including within Keratin 15+ populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity of taxane chemotherapy-induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy-induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell-protective therapy in taxane-based oncotherapy, and provides preclinical proof-of-principle in a healthy human (mini-) organ that G1 arrest therapy can limit taxane-induced hair follicle damage.

Bibliographical metadata

Original languageEnglish
JournalEMBO Molecular Medicine
Early online date12 Sep 2019
DOIs
Publication statusPublished - 1 Oct 2019