However, RAS mutations display a rare event, and other genetic or epigenetic alterations should be considered. MEK inhibitors U0126, AZD6244, and PD0325901. Furthermore, we found that MEK inhibitors exclusively induce apoptosis in Hut78 cells. Taken together, we Clindamycin palmitate HCl conclude that RAS mutations are rare events at a late stage of CTCL, and our preclinical results suggest that such late-stage patients profit from MEK inhibitors. Introduction Cutaneous T-cell lymphomas (CTCLs) are rare malignancies of skin-homing T lymphocytes. Curative modalities have thus far confirmed elusive. CTCL microarray studies have revealed natural clusters in association with prognosis.1 Array-based comparative genomic hybridization (CGH) combined with gene expression profiling identified highly recurrent chromosomal alterations both in mycosis fungoides (MF) and Szary syndrome (SS) patient specimens.2,3 For example, FASTK and SKAP1 gene loci showed recurrent gains, GLP-1 (7-37) Acetate and these genes also exhibited increased expression, whereas RB1 and DLEU tumor suppressor genes displayed diminished expression associated with loss. In another study, recurrent deletion of tumor suppressor genes BCL7A, SMAC/DIABLO, and RHOF in MF was observed.4 Genomic patterns characteristic of MF differ markedly from SS.5 This might implicate discriminative molecular pathogenesis and different therapeutic requirements. The RAS-RAF-MEK-ERK signaling pathway regulates cell responses to environmental stimuli and plays a crucial role in many cancers.6 Thus, RAF and MEK are attractive therapeutic targets.7,8 RAS is a small guanine-nucleotide binding protein that is attached to the inner side of the plasma membrane. Clindamycin palmitate HCl Activation of RAS causes RAF recruitment and activation by phosphorylation. Activated RAF kinase phosphorylates and activates MEK, which phosphorylates ERK. Three RAS (KRAS, NRAS, and HRAS), 3 RAF (ARAF, BRAF, and CRAF), 2 MEK (MEK1 and MEK2), and 2 ERK (ERK1 and ERK2) isoforms compose the canonical mitogen-activated protein kinase pathway. Somatic mutations that are found in Clindamycin palmitate HCl many cancers, including colon carcinoma, melanoma, or pancreatic cancer, occur almost exclusively in BRAF, KRAS, or NRAS isoforms.9C11 Common mutations affect glycine 12 (G12), glycine 13 (G13), or Clindamycin palmitate HCl glutamine 61 (Q61) and keep RAS in an activated form. The RAS pathway regulates survival, proliferation, senescence, and differentiation. However, in tumor cells, mutated (oncogenic) RAS preferentially promotes survival and proliferation. Thus, RAF and MEK kinases serve as suitable drug targets. RAF is usually targeted by inhibitors in preclinical or clinical development, including, for example, RAF265 and PLX4720.12,13 However, targeting the RAF pathway is complex because of the modes of pathway activation and regulation. Recently, it was shown that RAF265 and PLX4720 block MEK-ERK signaling and tumor growth only in cancers harboring a BRAFV600E mutation but not in wild-type BRAF or tumors with a KRAS mutation.12,14,15 Further, treating wild-type BRAF tumors with BRAFV600E specific inhibitors induced tumor growth in vitro and in vivo.14 Thus, MEK inhibitors Clindamycin palmitate HCl might be of interest in wild-type BRAF cells. Presently, these inhibitors are in dose-finding and early phase 2 studies.8,16,17 AZD6244, a nonCadenosine triphosphate-competitive specific MEK inhibitor, was evaluated in a phase 1 clinical trial and reached an appropriate safety profile for further studies.16 It interferes with epidermal homeostasis.18 In a phase 2 clinical trial, AZD6244 showed similar efficacy with respect to progression-free survival as control treatment.19 In a phase 2 clinical trial of 200 patients with melanoma patients, AZD6244 monotherapy resulted in lasting remissions, mainly in patients with documented BRAF mutations.20 Another specific inhibitor targeting MEK is PD0325901. PD0325901 treatment was shown to affect retinal function in clinical trials. Therefore, its development was discontinued.8 No extensive search for point mutations in CTCL has been reported so far. In the present study, we analyzed CTCL samples by a mass-spectrometric genotyping approach, termed OncoMap.21,22 This.
