Reference Detail

Ref Type

Journal Article

PMID

(26324360)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology	33	34	2015 Dec 01	4099-105	J Clin Oncol

URL

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.

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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