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Ref Type Journal Article
PMID (27870570)
Authors Ferrarotto R, Mitani Y, Diao L, Guijarro I, Wang J, Zweidler-McKay P, Bell D, William WN, Glisson BS, Wick MJ, Kapoun AM, Patnaik A, Eckhardt G, Munster P, Faoro L, Dupont J, Lee JJ, Futreal A, El-Naggar AK, Heymach JV
Title Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol 35
Issue 3
Date 2017 Jan 20
URL
Abstract Text Purpose Adenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with a subset demonstrating an aggressive phenotype. We investigated the molecular underpinnings of this phenotype and assessed the Notch1 pathway as a potential therapeutic target. Methods We genotyped 102 ACCs that had available pathologic and clinical data. Notch1 activation was assessed by immunohistochemistry for Notch1 intracellular domain. Luciferase reporter assays were used to confirm Notch1 target gene expression in vitro. The Notch1 inhibitor brontictuzumab was tested in patient-derived xenografts from patients with ACC and in a patient with ACC who was enrolled in a phase I study. Results NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr-rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro. NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining ( P = .004). NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype ( P < .001), advanced-stage disease at diagnosis ( P = .02), higher rate of liver and bone metastasis ( P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors. Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation. Furthermore, an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab. Conclusion NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors. Clinical studies targeting Notch1 in a genotype-defined ACC subgroup are warranted.

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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
FBXW7 W606* nonsense unknown FBXW7 W606* results in a premature truncation of the Fbxw7 protein at amino acid 606 of 707 (UniProt.org). W606* has been identified in the scientific literature (PMID: 27870570), but has not been biochemically characterized and therefore, its effect on Fbxw7 protein function is unknown (PubMed, Dec 2020).
NOTCH1 L1600Q missense unknown NOTCH1 L1600Q lies within the HD-N domain of the Notch1 protein (PMID: 16738328). L1600Q results in increased Notch1 signaling in a reporter assay in one study (PMID: 28820917), but does not result in statistically significant increase of Notch1 signaling in another study (PMID: 27870570), and therefore, its effect on Notch1 protein function is unknown.
NOTCH1 S1004L missense unknown NOTCH1 S1004L lies within the EGF-like domain 26 of the Notch1 protein (UniProt.org). S1004L has been identified in the scientific literature (PMID: 27870570), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Oct 2020).
NOTCH1 S2467fs frameshift unknown NOTCH1 S2467fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2467 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). S2467fs does not result in statistically significant increase of Notch1 signaling in a reporter assay (PMID: 27870570), but has not been fully characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Oct 2020).
NOTCH1 V1721G missense unknown NOTCH1 V1721G lies within the negative regulatory region of the Notch1 protein (PMID: 23072667). V1721G has been identified in the scientific literature (PMID: 27870570), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Oct 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 I1680N adenoid cystic carcinoma predicted - sensitive Brontictuzumab Preclinical - Pdx Actionable In a preclinical study, Brontictuzumab (OMP-52M51) inhibited tumor growth in a patient-derived xenograft model of adenoid cystic carcinoma harboring NOTCH1 I1680N (PMID: 27870570). 27870570
FBXW7 W606* NOTCH1 L1600Q NOTCH1 V1721G NOTCH1 S2467fs adenoid cystic carcinoma predicted - resistant Brontictuzumab Case Reports/Case Series Actionable In a clinical case study, FBXW7 W606* and NOTCH1 V1721G were identified at disease progression in a patient with metastatic adenoid cystic carcinoma harboring co-occurring NOTCH1 L1600Q and S2467fs who was treated with Brontictuzumab (OMP-52M51) (PMID: 27870570). 27870570
NOTCH1 L1600Q NOTCH1 S2467fs adenoid cystic carcinoma predicted - sensitive Brontictuzumab Case Reports/Case Series Actionable In a clinical case study, a patient with metastatic adenoid cystic carcinoma harboring co-occurring NOTCH1 L1600Q and S2467fs achieved a partial response after 2 doses of Brontictuzumab (OMP-52M51), however, his disease progressed shortly after treatment discontinuation (PMID: 27870570). 27870570
NOTCH1 S1004L adenoid cystic carcinoma no benefit Brontictuzumab Preclinical - Pdx Actionable In a preclinical study, Brontictuzumab (OMP-52M51) did not inhibit tumor growth in a patient-derived xenograft model of adenoid cystic carcinoma harboring NOTCH1 S1004L (PMID: 27870570). 27870570
FBXW7 W606* NOTCH1 L1600Q NOTCH1 V1721G NOTCH1 S2467fs adenoid cystic carcinoma no benefit Sunitinib Case Reports/Case Series Actionable In a clinical case study, Sutent (sunitinib) treatment resulted in rapid disease progression in a patient with metastatic adenoid cystic carcinoma harboring co-occurring NOTCH1 L1600Q and S2467fs, and acquired FBXW7 W606* and NOTCH1 V1721G (PMID: 27870570). 27870570