Phenylbutyrate suppresses distinct skin reactions that are enhanced by blockade of epidermal growth factor receptor signaling Yih-Lin Chung a,b, *, Newman N.M. Pui c a Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan b School of Medicine, National Yang-Ming University, Taipei, Taiwan c ASAN Laboratories, Inc., New Taipei City, Taiwan 1. Introduction Blockade of epidermal growth factor receptor (EGFR) by anti- EGFR antibodies and inhibition of the downstream EGFR tyrosine kinase activation cascade with tyrosine kinase inhibitors have been used as molecular targeted therapies against various malignancies to improve clinical outcomes [1]. However, over 50% of treated patients suffer from EGFR inhibitor (EGFRI)-mediated dermato- logical side effects that can include acneform rash, hyperpigmen- tation, xerotic skin, pruritus, pain, and skin fissures that localize predominantly to the seborrheic areas of the face and trunk within days or weeks of starting therapy [2]. The unpleasant effects of dermatological toxicity may reduce patient compliance and result in discontinuation of the EGFRI therapy [3]. Because the etiology remains unclear, there is currently no standard management or prophylaxis for these skin complications [4]. Thus, to increase quality of life and maintain adequate antineoplastic therapy, mechanistically driven strategies and agents are needed that decrease the EGFRI-induced skin reactions but do not interfere with the anti-EGFR effects on cancer cells. In addition to its prominent role in cancer cell growth, EGFR activation is involved in signaling that aids normal skin develop- ment, promotes wound healing, prevents apoptosis of keratinocytes, supports keratinocyte survival, and stimulates keratinocyte prolif- eration. Thus, development of a skin rash is viewed as a surrogate marker of EGFR blockade and anti-EGFR drug effectiveness in terms of killing tumor cells [5]. To date, no pathobiological mechanism has been identified as the cause of skin toxicities due to EGFR inhibition Journal of Dermatological Science 64 (2011) 163–173 A R T I C L E I N F O Article history: Received 17 May 2011 Received in revised form 9 August 2011 Accepted 17 August 2011 Keywords: Skin reaction Epidermal growth factor receptor inhibitor Histone deacetylase inhibitor Phenylbutyrate Mast cells CD4 + T cells A B S T R A C T Background: Epidermal growth factor receptor inhibitors (EGFRIs) cause skin inflammation, and understanding the factors that mediate this reaction is fundamental for designing therapies for EGFRI- related cutaneous side effects. Objective: We characterized EGFRI-enhanced skin reactions and evaluated the therapeutic efficacy of phenylbutyrate, a histone deacetylase inhibitor. Methods: PD168393, an EGFRI, was applied topically to the ear skin of mice with or without mast cell deficiency. The skin was then irritated once or pre-sensitized and repeatedly challenged with 2,4- dinitrofluorobenzene (DNFB). The reaction pattern, the type and number of infiltrating cells, changes in protein, cytokine (TNF-a) and chemokine (CCL2) expression, and the immune response were analyzed. Phenylbutyrate, formulated as a gel for topical treatment or dissolved in water for intraperitoneal administration, was tested as a treatment. Results: EGFRI rapidly upregulated the mast cell chemotactic factor, stem cell factor (SCF) and augmented DNFB-induced immediate contact dermatitis within hours of treatment in the presence of mast cells. Topical phenylbutyrate treatment suppressed EGFRI-induced SCF expression in the epithelium, inhibited DNFB-induced mast cell recruitment in the dermis, and ameliorated the EGFRI-enhanced acute skin reaction. EGFRI also enhanced the delayed-type DNFB-induced hypersensitive reaction that was mast-cell independent but was associated with T lymphocytes. Systemic phenylbutyrate administration suppressed EGFRI-enhanced delayed-type skin hypersensitivity by increasing the number and function of Foxp3 + T regulatory suppressor cells, which inhibited T helper cell proliferation. Conclusions: Our data suggest that phenylbutyrate has dual beneficial therapeutic effects on EGFRI- enhanced acute (local inflammatory) and late (systemic immune) skin reactions. ß 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. * Corresponding author at: Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, No. 125 Lih-Der Road, Pei-Tou district, Taipei 112, Taiwan. Tel.: +886 2 28970011; fax: +886 2 28586134. E-mail address: ylchung@kfsyscc.org (Y.-L. Chung). Contents lists available at SciVerse ScienceDirect Journal of Dermatological Science jou r nal h o mep ag e: w ww .elsevier .co m /jds 0923-1811/$36.00 ß 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2011.08.007