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|Ref Type||Journal Article|
|Authors||Grisham RN, Sylvester BE, Won H, McDermott G, DeLair D, Ramirez R, Yao Z, Shen R, Dao F, Bogomolniy F, Makker V, Sala E, Soumerai TE, Hyman DM, Socci ND, Viale A, Gershenson DM, Farley J, Levine DA, Rosen N, Berger MF, Spriggs DR, Aghajanian CA, Solit DB, Iyer G|
|Title||Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer.|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|MAP2K1||Q56_V60del||deletion||gain of function||MAP2K1 Q56_V60del results in the deletion of five amino acids in the protein kinase domain of the Map2k1 protein from amino acids 56 to 60 (UniProt.org). Q56_V60del confers a gain of function to the Map2k1 protein as indicated by transformation capabilities and increased phosphorylation of Erk and S6k in culture (PMID: 26324360).|
|RB1||S758L||missense||unknown||RB1 S758L lies within domain B of the Rb1 protein (UniProt.org). S758L has been identified in the scientific literature (PMID: 26324360), but has not been biochemically characterized and therefore, its effect on Rb1 protein function is unknown (PubMed, Nov 2023).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|MAP2K1 Q56_V60del||ovarian serous carcinoma||predicted - sensitive||Selumetinib||Case Reports/Case Series||Actionable||In a Phase II trial, Koselugo (selumetinib) treatment resulted in a complete response that lasted over 5 years with continuous treatment in a patient with serous ovarian cancer harboring MAP2K1 Q56_V60del (PMID: 26324360).||26324360|