Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer
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Published on: July 25, 2020
Rachel N Grisham1, Brooke E Sylvester2, Helen Won2
1Rachel N. Grisham, Brooke E. Sylvester, Helen Won, Deborah DeLair, Zhan Yao, Ronglai Shen, Fanny Dao, Faina Bogomolniy, Vicky Makker, Evis Sala, Tara E. Soumerai, David M. Hyman, Douglas A. Levine, Neal Rosen, Michael F. Berger, David R. Spriggs, Carol A. Aghajanian, David B. Solit, and Gopa Iyer, Memorial Sloan Kettering Cancer Center; Rachel N. Grisham, Gregory McDermott, Vicky Makker, David M. Hyman, Neal Rosen, Michael F. Berger, David R. Spriggs, Carol A. Aghajanian, David B. Solit, and Gopa Iyer, Weill Cornell Medical College; Ricardo Ramirez, Graduate School of Medical Sciences; Nicholas D. Socci and Agnes Viale, Michael F. Berger, and David B. Solit, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, New York, NY; David M. Gershenson, University of Texas MD Anderson Cancer Center, Houston, TX; and John Farley, St Joseph's Hospital and Medical Center, Phoenix, AZ. grishamr@mskcc.org.
Purpose:
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.
Patients And Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Researchers identified a novel MEK1 gene deletion in a patient with low-grade serous ovarian cancer who had a durable response to MEK inhibitor therapy. This finding suggests that alterations in the mitogen-activated protein kinase pathway are common in this cancer type.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic low-grade serous (LGS) ovarian cancer lacks effective systemic therapies.
- Mutations in BRAF and KRAS are frequent in LGS ovarian cancers, and MEK inhibition shows limited efficacy.
- Identifying biomarkers for MEK inhibitor sensitivity is crucial for LGS ovarian cancer treatment.
Observation:
- An outlier patient with LGS ovarian cancer achieved a durable complete response (>5 years) to selumetinib, a MEK inhibitor.
- Next-generation sequencing of this patient's tumor revealed a novel 15-nucleotide deletion in the MAP2K1 gene (encoding MEK1).
- This MEK1 deletion mutant activated the extracellular signal-regulated kinase (ERK) pathway and promoted tumor growth in preclinical models.
Findings:
- The identified MEK1 deletion mutant retained sensitivity to selumetinib.
- Analysis of 28 additional LGS/SB tumors revealed pathway-activating mutations in 82%, including BRAF fusions.
- One patient with a BRAF fusion achieved a complete response to combination MEK inhibitor therapy.
Implications:
- Activating alterations in the mitogen-activated protein kinase (MAPK) pathway are prevalent in LGS ovarian cancer.
- Next-generation sequencing can detect novel deletions and fusions missed by older methods.
- These findings support further clinical investigation of MEK inhibitors for LGS ovarian cancer, particularly in patients with specific MAPK pathway alterations.
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