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

Talveen S. Purba, Kayumba Ng'andu, Lars Brunken, Eleanor Smart, Ellen Mitchell, Nashat Hassan, Aaron O'Brien, Charlotte Mellor, Jennifer Jackson, Asim Shahmalak, Ralf Paus

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Taxanes are a leading cause of severe and often 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+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence 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 tissue damage.

Original languageEnglish (US)
Article numbere11031
JournalEMBO Molecular Medicine
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2019

Keywords

  • chemotherapy
  • hair loss
  • palbociclib
  • taxol
  • taxotere

ASJC Scopus subject areas

  • Molecular Medicine

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