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

EMBO Mol Med. 2019 Oct;11(10):e11031. doi: 10.15252/emmm.201911031. Epub 2019 Sep 12.

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.

Keywords: chemotherapy; hair loss; palbociclib; taxol; taxotere.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alopecia / chemically induced*
  • Alopecia / prevention & control*
  • Antineoplastic Agents / adverse effects*
  • Bridged-Ring Compounds / adverse effects*
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Docetaxel / adverse effects
  • Humans
  • Keratinocytes / drug effects
  • Models, Theoretical
  • Organ Culture Techniques
  • Paclitaxel / adverse effects
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology
  • Stem Cells / drug effects*
  • Taxoids / adverse effects*

Substances

  • Antineoplastic Agents
  • Bridged-Ring Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Taxoids
  • Docetaxel
  • taxane
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib
  • Paclitaxel