Transient p53/p21 activation selectively protects healthy human hair follicles and their stem cells from chemotherapy
Jennifer Gherardini, Tara Samra, Tatiana Gomez-Gomez, Aysun Akhundlu, Samantha D. Verling, Kinga Linowiecka, Tongyu C. Wikramanayake, Ulrich Knie, Jose Rodríguez-Feliz, Ramtin Kassir, Wolfgang Funk, Reza P. Azar, D. Allen Annis, Manuel Aivado, Jérémy Chéret, Ralf Paus
Jennifer Gherardini, Tara Samra, Tatiana Gomez-Gomez, Aysun Akhundlu, Samantha D. Verling, Kinga Linowiecka, Tongyu C. Wikramanayake, Ulrich Knie, Jose Rodríguez-Feliz, Ramtin Kassir, Wolfgang Funk, Reza P. Azar, D. Allen Annis, Manuel Aivado, Jérémy Chéret, Ralf Paus
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Research Article Dermatology

Transient p53/p21 activation selectively protects healthy human hair follicles and their stem cells from chemotherapy

Abstract

Chemotherapy-induced alopecia (CIA) remains one of the most distressing adverse effects of cancer therapy. Yet, no therapy is available to selectively protect healthy hair follicles (HFs) and their epithelial stem cells (eHFSCs) from chemotherapy-induced damage without awarding potential survival benefits to cancer cells. Here, we report how human HFs can be protected against 2 lead CIA-inducing chemotherapeutics by inducing selective transient cell cycle arrest. Pretreating scalp HFs before chemotherapy exposure ex vivo with ALRN-6924, a clinical-stage “stapled peptide” drug that binds with high affinity to key endogenous inhibitors of p53, selectively activated p53 signaling only in cells with wild-type TP53 genotype and upregulated p21. This led to temporary cell cycle arrest in healthy tissues without protecting TP53-mutant cancer cells and mitigated chemotherapy-induced HF damage on multiple levels, including excessive hair matrix apoptosis, premature catagen, pigmentary abnormalities, “mitotic catastrophe,” and micronucleation. It also protected eHFSCs against DNA damage, apoptosis, and pathological epithelial-mesenchymal transition. Notably, even topically applied ALRN-6924 afforded relative chemotherapy protection ex vivo. These results provide proof of principle for a strategy to selectively protect rapidly proliferating healthy epithelial tissues and their stem cells in patients with TP53-mutant cancers, which promises to protect against acute and permanent CIA.

Authors

Jennifer Gherardini, Tara Samra, Tatiana Gomez-Gomez, Aysun Akhundlu, Samantha D. Verling, Kinga Linowiecka, Tongyu C. Wikramanayake, Ulrich Knie, Jose Rodríguez-Feliz, Ramtin Kassir, Wolfgang Funk, Reza P. Azar, D. Allen Annis, Manuel Aivado, Jérémy Chéret, Ralf Paus

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Figure 2

ALRN-6924 reduces PTX- or 4-HC–induced damage of the anagen hair matrix and promotes “dystrophic anagen” in the microdissected HF.

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ALRN-6924 reduces PTX- or 4-HC–induced damage of the anagen hair matrix ...
(A) Experimental design scheme. (B–L) Quantitative (immuno-)histomorphometry and representative images showing the hair follicle damage induced by PTX and 4-HC and the protective role of ALRN-6924. (B and J) Percentage of caspase-3+ cells in the hair matrix. (C) Number of cells in mitotic catastrophe, caspase-3+Ki-67+ cells in the hair matrix. (D and K) Representative images of Ki-67/caspase-3 double staining. (E and F) Number of micronucleated bodies and representative images of DAPI+ nuclei. (G and I) Hair cycle staging showing the percentage of HFs in each stage. (H and L) Number and representative images of melanin clumps in the defined reference area. Mean ± SEM; N = 22–24 HF/group from 3 donors treated with PTX or 4-HC. Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Green arrows: caspase-3+ cells; orange arrows: mitotic catastrophe; caspase-3+Ki-67+ cells; white arrows: micronucleated bodies. Note that the vehicle and ALRN-6924 data in graphs B, G–J, and L were used to generate the graphs presented in Figure 1, F, H, and I.