pyrimidinones and Histiocytosis--Langerhans-Cell

The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.

Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Asian People; Histiocytosis, Langerhans-Cell; Humans; Liver Neoplasms; Lung Neoplasms; MAP Kinase Kinase 1; Mice; Mutation; Neoplasms; NIH 3T3 Cells; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

Topics: Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Kinase 1; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Activating variants of the MAPK pathway have been found in some Langerhans cell histiocytosis (LCH) lesions. Inhibition of the MAPK pathway with trametinib (MEK inhibitor) has been shown to induce responses in LCH patients. Two adolescent males with LCH driven by BRAF p.N486_P490del have received trametinib for >1 year with no reactivation in one and partial response in another (including stable lung disease). A third male with neonatal LCH and MAP2K1p.K57_G61del had a complete response to trametinib with no active disease after 22 months. All patients continue on trametinib monotherapy with tolerable skin and creatine phosphokinase toxicity.

Topics: Adolescent; Adult; Antineoplastic Agents; Gene Deletion; Histiocytosis, Langerhans-Cell; Humans; Male; MAP Kinase Kinase 1; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

Topics: Adolescent; Antineoplastic Agents; Histiocytosis, Langerhans-Cell; Humans; Lung; Male; MAP Kinase Kinase 1; Pyridones; Pyrimidinones; Tomography, X-Ray Computed; Treatment Outcome

Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance.

Topics: Adolescent; Adrenal Cortex Hormones; Butadienes; Combined Modality Therapy; Cytarabine; Disease Progression; Drug Resistance; Drug Therapy, Combination; Enzyme Activation; Exons; HEK293 Cells; Hematopoietic Stem Cell Transplantation; Histiocytosis, Langerhans-Cell; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Molecular Targeted Therapy; Mutation; Nitriles; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrazoles; Pyridones; Pyrimidinones; Recombinant Fusion Proteins; Sequence Deletion; Thiophenes; Vincristine

Langerhans cell histiocytosis (LCH) is now understood to be a neoplastic disease in which over 50% of cases have somatic activating mutations of BRAF. However, the extracellular signal-related (ERK) pathway is activated in all cases including those with wild type BRAF alleles. Here, we applied a targeted massively parallel sequencing panel to 30 LCH samples to test for the presence of additional genetic alterations that might cause ERK pathway activation. In 20 BRAF wild type samples, we found 3 somatic mutations in MAP2K1 (MEK1) including C121S and C121S/G128D in the kinase domain, and 56_61QKQKVG>R, an in-frame deletion in the N-terminal regulatory domain. All three variant proteins constitutively phosphorylated ERK in in vitro kinase assays. The C121S/G128D and 56_61QKQKVG>R variants were resistant to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib in vitro. Within the entire sample set, we found 3 specimens with mutations in MAP3K1 (MEKK1), including two truncation mutants, T779fs and T1481fs; T1481fs encoded an unstable and nonfunctional protein when expressed in vitro. T779fs was present in a specimen carrying BRAF V600E. The third variant was a single nucleotide substitution, E1286V, which was fully functional and is likely a germline polymorphism. These results indicate that LCH cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which, in the case of MAP2K1, may be responsible for ERK activation in a wild type BRAF setting. The resistance of some of these variants to trametinib may also have clinical implications for the combined use of RAF and MEK inhibitors in LCH.

Topics: Antineoplastic Agents; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase Kinase 1; Mutation; Phosphorylation; Pyridones; Pyrimidinones; Signal Transduction