Reference Detail

Ref Type Journal Article
PMID (25104330)
Authors Stoeck A, Lejnine S, Truong A, Pan L, Wang H, Zang C, Yuan J, Ware C, MacLean J, Garrett-Engele PW, Kluk M, Laskey J, Haines BB, Moskaluk C, Zawel L, Fawell S, Gilliland G, Zhang T, Kremer BE, Knoechel B, Bernstein BE, Pear WS, Liu XS, Aster JC, Sathyanarayanan S
Title Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma.
Journal Cancer discovery
Vol 4
Issue 10
Date 2014 Oct
URL
Abstract Text Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD-low tumors without NOTCH1 mutations were resistant.NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
A1552G missense gain of function - predicted NOTCH1 A1552G lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). A1552G is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
A1552V missense gain of function - predicted NOTCH1 A1552V lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). A1552V is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
A1570G missense gain of function - predicted NOTCH1 A1570G lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). A1570G is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
A1707T missense gain of function - predicted NOTCH1 A1707T lies within the extracellular domain of the Notch1 protein (UniProt.org). A1707T is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
E1567K missense no effect - predicted NOTCH1 E1567K lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). E1567K demonstrates signaling activity similar to wild-type Notch1 in an in-vitro reporter assay (PMID: 25104330) and therefore, is predicted to have no effect on Notch1 protein function.
I1680S missense gain of function - predicted NOTCH1 I1680S lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). I1680S is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
R1627L missense gain of function - predicted NOTCH1 R1627L lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). R1627L is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
R1683W missense gain of function - predicted NOTCH1 R1683W lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). R1683W is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
R365H missense unknown NOTCH1 R365H lies within the calcium-binding EGF-like domain 9 of the Notch1 protein (UniProt.org). R365H is not associated with increased nuclear NICD expression in patient-derived xenograft models (PMID: 25104330), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Feb 2019).
V1575A missense gain of function - predicted NOTCH1 V1575A lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). V1575A is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
V1599M missense gain of function - predicted NOTCH1 V1599M lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). V1599M is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
V1676I missense gain of function - predicted NOTCH1 V1676I lies within the negative regulatory region of the Notch1 protein (PMID: 25104330). V1676I is predicted to confer a gain of function to the Notch1 protein, as demonstrated by increased Notch1 signaling in an in-vitro reporter assay (PMID: 25104330).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 wild-type triple-receptor negative breast cancer no benefit MRK-003 + Paclitaxel Preclinical Actionable In a preclinical study, the combination of MRK-003 and Taxol (paclitaxel) did not potentiate the anti-tumor effects compared to single agent therapy in triple receptor-negative breast cancer xenograft models harboring wild-type NOTCH1 (PMID: 25104330). 25104330
NOTCH1 I1680S osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 I1680S in culture (PMID: 25104330). 25104330
NOTCH1 rearrange triple-receptor negative breast cancer no benefit MRK-003 + SCH772984 Preclinical Actionable In a preclinical study, SCH772984 did not potentiate the growth inhibition effect of MRK-003 in triple receptor-negative breast cancer cells harboring NOTCH1 rearrangement in culture (PMID: 25104330). 25104330
NOTCH1 rearrange triple-receptor negative breast cancer sensitive MRK-003 + Paclitaxel Preclinical Actionable In a preclinical study, MRK-003 and Taxol (paclitaxel) worked synergistically to inhibit tumor growth in triple receptor-negative breast cancer xenograft models harboring NOTCH1 rearrangement, resulting in tumor regression (PMID: 25104330). 25104330
NOTCH1 rearrange triple-receptor negative breast cancer sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited growth of triple receptor-negative breast cancer cells harboring NOTCH1 rearrangement in culture and reduced tumor growth in xenograft models (PMID: 25104330). 25104330
NOTCH1 V1676I osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 V1676I in culture (PMID: 25104330). 25104330
NOTCH1 A1552G osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 A1552G in culture (PMID: 25104330). 25104330
NOTCH1 A1552V osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 A1552V in culture (PMID: 25104330). 25104330
NOTCH1 V1575A osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 V1575A in culture (PMID: 25104330). 25104330
NOTCH1 wild-type triple-receptor negative breast cancer decreased response MRK-003 Preclinical Actionable In a preclinical study, triple receptor-negative breast cancer xenograft models harboring wild-type NOTCH1 demonstrated reduced sensitivity to MRK-003 induced tumor growth inhibition (PMID: 25104330). 25104330
NOTCH1 E1567K osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 E1567K in culture (PMID: 25104330). 25104330
NOTCH1 R1683W osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 R1683W in culture (PMID: 25104330). 25104330
NOTCH1 V1599M osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 V1599M in culture (PMID: 25104330). 25104330
NOTCH1 A1570G osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 A1570G in culture (PMID: 25104330). 25104330
NOTCH1 A1707T Advanced Solid Tumor sensitive MRK-003 Preclinical Actionable In a preclinical study, transformed cells expressing NOTCH1 A1707T demonstrated sensitivity to MRK-003 in culture (PMID: 25104330). 25104330
NOTCH1 A1707T osteosarcoma sensitive MRK-003 Preclinical Actionable In a preclinical study, MRK-003 inhibited Notch1 signaling in a luciferase reporter assay in osteosarcoma cell lines overexpressing NOTCH1 A1707T in culture (PMID: 25104330). 25104330