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Study Explores Link Between MAPK Pathway Alteration and Long-Term Response to MEK Inhibitor in Serous Ovarian Cancer

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Key Points

  • The tumor in a patient with a remarkable response to MEK inhibitor treatment harbored a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1.
  • Mutations predicted to induce extracellular signal-regulated kinase pathway activation were identified in the majority of tumors.

In a study reported in the Journal of Clinical Oncology, Grisham et al identified a novel alteration in the MAP2K1 gene encoding for MEK1 that appeared to explain a complete response ongoing for more than 5 years in a patient treated with the MEK inhibitor selumetinib for metastatic low-grade serous ovarian cancer. MEK inhibition has been shown to result in tumor regression in a minority of patients with serous borderline and low-grade serous ovarian cancers, but no correlation between mutation status and clinical response has been identified.

Mutations Identified

In the study, next-generation sequencing was used to analyze the outlier patient’s tumor and an additional 28 serous borderline/low-grade serous tumors. Analysis of the outlier patient’s tumor revealed a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. This mutant-induced extracellular signal–regulated kinase pathway activation promoted anchorage-independent growth and tumor formation in mice and retained sensitivity to selumetinib. Mutations predicted to induce extracellular signal–regulated kinase pathway activation were also identified in 23 (82%) of the other serous borderline/low-grade serous tumors; they included tumors from two patients with BRAF fusions, with one having an ongoing complete response to combination therapy including a MEK inhibitor.

The investigators concluded, “Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with low-grade serous 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 low-grade serous ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.”

Rachel Grisham, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.

The study was supported by Cycle for Survival, Laura Mercier Ovarian Cancer Fund, Kaleidoscope of Hope Foundation, Ovarian Cancer Research Fund, Starr Foundation, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, and Integrated Genomics Operation Core, funded by the National Cancer Institute. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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