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

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

doi:10.15252/emmm.201911031

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.

Highlights

Chemotherapy-induced alopecia is a highly distressing adverse effect of cancer treatment and can persist long after the completion of chemotherapy treatment regimens (Paus et al, 2013)
These results reveal that taxanes promote the abnormal accumulation of mitotic keratinocytes in the hair matrix, signifying mitotic arrest, without affecting G1/S cell cycle progression (Fig 1Ei–iii)
We provide the first proof-of-principle that arresting hair matrix keratinocytes and hair follicle epithelial stem/progenitor cells in G1, using the CDK4/6-inhibitor palbociclib, provides relative protection from taxane-induced hair follicle damage without promoting catagen development or exerting additional hair follicle toxicity

Summary

Introduction

Chemotherapy-induced alopecia is a highly distressing adverse effect of cancer treatment and can persist long after the completion of chemotherapy treatment regimens (Paus et al, 2013). The only currently available preventive treatment for chemotherapy-induced alopecia is scalp cooling, whose clinical efficacy is as yet unsatisfactory and difficult to predict, especially with taxane chemotherapy-induced alopecia (Friedrichs & Carstensen, 2014; Cigler et al, 2015; Rugo et al, 2017; Rice et al, 2018). Novel and effective chemotherapy-induced alopecia prevention strategies need to be urgently developed and translated into clinical practice. This can only be achieved through the generation of promising preclinical data in appropriate human models that are as close as possible to clinical chemotherapy-induced alopecia (Bodoet al, 2007, 2009; Paus et al, 2013; Bohm et al, 2014; Sharova et al, 2014; Yoon et al, 2016)

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