title: Fas/Fas ligand mediates keratinocyte death in sunitinib-induced hand-foot skin reaction.
abstract: Sunitinib, a multitargeted receptor Y kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among the 29 biomarkers examined, soluble FasL (sFasL) showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with those of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40 mg kg(-1) per day) for 4 weeks to mice caused the maximally affected skin area with an erosion-to-ulceration response to tape-stripping. The skin biopsies of mice administered sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR.
authors.affiliation: GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, College of Medicine, Chang Gung University, Keelung, Linkou, and Taipei, Taiwan.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, College of Medicine, Chang Gung University, Keelung, Linkou, and Taipei, Taiwan.
authors.forename: Shih-Chi
authors.initials: SC
authors.lastname: Su
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Yen-Yang
authors.initials: YY
authors.lastname: Chen
authors.affiliation: GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chi-Tung
authors.initials: CT
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, College of Medicine, Chang Gung University, Keelung, Linkou, and Taipei, Taiwan.
authors.forename: Rosaline
authors.initials: R
authors.lastname: Chung-Yee Hui
authors.affiliation: GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Tsung-Wen
authors.initials: TW
authors.lastname: Chen
authors.affiliation: GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yi-Yin
authors.initials: YY
authors.lastname: Jan
authors.affiliation: Department of Pharmacology, Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chien-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Dermatology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ting-Jui
authors.initials: TJ
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, College of Medicine, Chang Gung University, Keelung, Linkou, and Taipei, Taiwan. Electronic address: sihung@ym.edu.tw.
authors.forename: Chih-Hsun
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: r2925a@adm.cgmh.org.tw.
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D016923:Cell Death; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004890:Erythema / Q000139:chemically induced* / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000097:blood / Q000378:metabolism*; D005260:Female; D005528:Foot / Q000473:pathology; D005786:Gene Expression Regulation; D006225:Hand / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D015603:Keratinocytes / Q000166:cytology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D011758:Pyrroles / Q000737:chemistry*; D000077210:Sunitinib; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D053222:Fas Ligand Protein; D007211:Indoles; D011758:Pyrroles; D019014:fas Receptor; D000077210:Sunitinib