Mechanisms of skin aging induced by EGFR inhibitors

Abstract

BACKGROUND The mechanisms of skin aging have not been completely elucidated. Anecdotal data suggests that EGFR inhibition accelerates aging-like skin changes. OBJECTIVE To evaluate the clinical characteristics and investigate the cellular and molecular mechanisms underlying skin changes associated with the use of EFGRIs. PATIENTS AND METHODS Patients during prolonged treatment with EGFRIs (>3 months) were analyzed for aging-like skin changes. Baseline EGFR expression was compared in young (< 25 years old) vs. old (> 65 years old) skin. In addition, the regulation of extracellular matrix, senescence-associated genes, and cell cycle status was measured in primary human keratinocytes treated with erlotinib in vitro. RESULTS Progressive signs of skin aging, including xerosis cutis, atrophy, rhytide formation and/or actinic purpura in 12 patients. Keratinocytes treated with erlotinib in vitro showed a significant down-modulation of hyaluronan synthases (HAS2 and HAS3), whereas senescence-associated genes (p21, p53, IL-6, maspin) were upregulated, along with a G1 cell cycle arrest and stronger SA β-Gal activity. There was significantly decreased baseline expression in EGFR-density in aged skin, when compared to young controls. CONCLUSIONS EGFR inhibition results in molecular alterations in keratinocytes that may contribute to the observed skin aging of patients treated with respective targeted agents.

Photoageing‐related skin changes in different age groups: a clinical evaluation by biophysical and imaging techniques

“…Other studies have shown the need of skin care in terms of sun exposure from the first years of age, since signs like fine wrinkles and skin hyperpigmentation were observed in young skin with a high frequency of solar exposure .…”

A survey of patient and physician acceptance of skin toxicities from anti-epidermal growth factor receptor therapies

“…EGFR inhibitor-elicited skin toxicities begin as edema and erythema during the first weeks of therapy, followed by acneiform eruptions and crusting, and ultimately paronychia and fissure [ 9 , 10 ]. Other dermatologic AEs (dAEs) that can accompany EGFR inhibitor therapy include skin aging, xerosis, hair changes, and pruritus [ 11 – 13 ]. These skin toxicities can be painful and debilitating, thereby potentially affecting patients’ quality of life (QoL) and adherence to therapy [ 12 – 16 ].…”

The role of EGFR signaling in age‐related osteoporosis in mouse cortical bone

“…Inactivating it in mice by EGFR-specific inhibitors or knockdown of EGFR in osteoprogenitors and osteoblastic cells results in bone loss because of a decreased number of bone marrow mesenchymal progenitors (18). Recently, it was reported that EGFR signaling protected cells from senescence and inhibited tissue aging (19)(20)(21), and blocking EGFR signaling promoted cell senescence and tissue aging (21). These studies strongly suggest that the EGFR signaling in osteoprogenitors might be important in prevention of cell senescence and regulation of cortical bone metabolism.…”