Continuous MEK Inhibition by AZD6244 Results in Exhaustion of the Cutaneous Keratinocytic Stem Cell Pool and Resembles Senescence Driven Skin Aging

The study investigated the effects of AZD6244, a MEK inhibitor, on skin conditions in 28 patients with unresectable stage III/IV melanoma. The treatment led to significant cutaneous toxicities, with 86.3% of patients experiencing skin eruptions and 77.2% developing acute papulopustular rashes. Chronic skin changes included xerosis, paronychia, and pulpitis sicca, similar to effects seen with EGFR inhibitors. Additionally, hair depigmentation and vitiligo were observed, but not alopecia or other hair abnormalities typical of EGFR inhibitors. Histological analysis showed apoptotic keratinocytes and changes in keratinocyte proliferation, suggesting that continuous MEK inhibition by AZD6244 exhausted the cutaneous keratinocytic stem cell pool, resembling skin aging.