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High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade
- Source :
- Blood. 117(8)
- Publication Year :
- 2011
-
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 KRASG13D mutation; one Sézary syndrome and one CD30+ CTCL harbored a NRASQ61K 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 NRASQ61K 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 NRASQ61K 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.
- Subjects :
- Neuroblastoma RAS viral oncogene homolog
medicine.medical_specialty
CD30
T cell
Biopsy
Immunology
Biology
medicine.disease_cause
Biochemistry
Proto-Oncogene Proteins p21(ras)
Mycosis Fungoides
Internal medicine
hemic and lymphatic diseases
Proto-Oncogene Proteins
medicine
Humans
Sezary Syndrome
Protein Kinase Inhibitors
Neoplasm Staging
Mitogen-Activated Protein Kinase Kinases
Mutation
Mycosis fungoides
Hematology
Lymphoid Neoplasia
Cell Biology
medicine.disease
Molecular biology
Lymphoma
High-Throughput Screening Assays
Lymphoma, T-Cell, Cutaneous
medicine.anatomical_structure
Cancer research
ras Proteins
raf Kinases
KRAS
Signal Transduction
Subjects
Details
- ISSN :
- 15280020
- Volume :
- 117
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....ff9ecd4723abb7dbc61e47685a1fc43d