Steroids and immunosuppressive agents potentiate the cytotoxicity of the EGFR inhibitor erlotinib (E) in human skin keratinocytes whereas Vit K3 exerts a protective effect: Implications for the management of the skin rash

Abstract

9124 Background: Skin toxicity secondary to EGFR inhibitors is treated symptomatically with topical and systemic combinations of steroids, antibiotics, antihistamines, and immunosuppressive agents with variable and often unsatisfactory results. Vit K3 prevents EGFR inhibition induced by E and cetuximab in human A431 tumor cells, probably through an effect on the phosphatase (Perez-Soler, ASCO 2006). We studied the cytotoxic effects of different agents used to treat the EGFR inhibitor-mediated skin rash on human immortalized skin keratinocytes exposed to the EGFR inhibitor E as well as the potential protective effect of Vit K3. Methods: The cytotoxicity of E in the presence of non cytotoxic concentrations of hydrocortisone, minocycline, cyclosporine-A, diphenhydramine, and Vit K3 was assessed by MTT assay in human HaCat cells, a cell line derived from human basal epidermal cells. Results: E cytotoxicity was enhanced by 2–5 fold by cyclosporine A and hydrocortisone, not affected by minocycline and diphenhydramine, and reduced by 5-fold by Vit K3. Vit K3 25–50 μM induced EGFR activation and prevented E's inhibitory effect on EGFR. Conclusions: Steroids and immunosuppressive agents may potentiate the cytotoxic effect of anti-EGFR agents in the skin, thus providing a possible explanation for the erratic and mixed therapeutic results often observed with the use of these agents. Vit K3 was the only agent capable of abrogating the cytotoxic effect of E in this clinically relevant model of normal human skin. A topical formulation of Vit K3 is undergoing preclinical evaluation. Supported by NCI CA 91784 and 113630 and a grant from Hana Biosciences. No significant financial relationships to disclose.