title: High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade.
abstract: Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing lymphoid cells, which have so far not been investigated thoroughly for common oncogenic mutations. We screened 90 biopsy specimens from CTCL patients (41 mycosis fungoides, 36 Sézary syndrome, and 13 non-mycosis fungoides/Sézary syndrome CTCL) for somatic mutations using OncoMap technology. We detected oncogenic mutations for the RAS pathway in 4 of 90 samples. One mycosis fungoides and one pleomorphic CTCL harbored a KRAS(G13D) mutation; one Sézary syndrome and one CD30(+) CTCL harbored a NRAS(Q61K) amino acid change. All mutations were found in stage IV patients (4 of 42) who showed significantly decreased overall survival compared with stage IV patients without mutations (P = .04). In addition, we detected a NRAS(Q61K) mutation in the CTCL cell line Hut78. Knockdown of NRAS by siRNA induced apoptosis in mutant Hut78 cells but not in CTCL cell lines lacking RAS mutations. The NRAS(Q61K) mutation sensitized Hut78 cells toward growth inhibition by the MEK inhibitors U0126, AZD6244, and PD0325901. Furthermore, we found that MEK inhibitors exclusively induce apoptosis in Hut78 cells. Taken together, we 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.
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Kiessling
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Oberholzer
authors.forename: Chandrani
authors.initials: C
authors.lastname: Mondal
authors.forename: Maria B
authors.initials: MB
authors.lastname: Karpova
authors.forename: Marie C
authors.initials: MC
authors.lastname: Zipser
authors.forename: William M
authors.initials: WM
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Girardi
authors.forename: Laura E
authors.initials: LE
authors.lastname: Macconaill
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Kehoe
authors.forename: Charlie
authors.initials: C
authors.lastname: Hatton
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Gernot
authors.initials: G
authors.lastname: Polier
authors.forename: Dorothee
authors.initials: D
authors.lastname: Süss
authors.forename: Claus-Detlev
authors.initials: CD
authors.lastname: Klemke
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Karsten
authors.initials: K
authors.lastname: Gülow
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D001706:Biopsy; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D009182:Mycosis Fungoides; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012751:Sezary Syndrome; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D048490:raf Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins