azd-6244 and Carcinoma--Ovarian-Epithelial

azd-6244 has been researched along with Carcinoma--Ovarian-Epithelial* in 1 studies

Other Studies

1 other study(ies) available for azd-6244 and Carcinoma--Ovarian-Epithelial

ArticleYear
Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015, Dec-01, Volume: 33, Issue:34

    No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor.. Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed.. Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy.. Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.

    Topics: Animals; Benzimidazoles; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous; Drug Resistance, Neoplasm; Female; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; MAP Kinase Kinase 1; Mice; Middle Aged; Mutation; Neoplasm Grading; Neoplasms, Glandular and Epithelial; NIH 3T3 Cells; Ovarian Neoplasms; Prognosis; Tumor Stem Cell Assay

2015