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Ref Type Journal Article
PMID (25564152)
Authors Wang K, Zhang Q, Li D, Ching K, Zhang C, Zheng X, Ozeck M, Shi S, Li X, Wang H, Rejto P, Christensen J, Olson P
Title PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 21
Issue 6
Date 2015 Mar 15
URL
Abstract Text To identify and characterize novel, activating mutations in Notch receptors in breast cancer and to determine response to the gamma secretase inhibitor (GSI) PF-03084014.We used several computational approaches, including novel algorithms, to analyze next-generation sequencing data and related omic datasets from The Cancer Genome Atlas (TCGA) breast cancer cohort. Patient-derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with PF-03084014. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by PF-03084014.We identified mutations within and upstream of the PEST domains of NOTCH1, NOTCH2, and NOTCH3 in the TCGA dataset. Mutations occurred via several genetic mechanisms and compromised the function of the PEST domain, a negative regulatory domain commonly mutated in other cancers. Focal amplifications of NOTCH2 and NOTCH3 were also observed, as were heterodimerization or extracellular domain mutations at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple-negative breast cancer subtype (TNBC). PDX models were also identified that harbored PEST domain mutations, and these models were highly sensitive to PF-03084014.This work suggests that Notch-altered breast cancer constitutes a bona fide oncogenic driver segment with the most common alteration being PEST domain mutations present in multiple Notch receptors. Importantly, functional studies suggest that this newly identified class can be targeted with Notch inhibitors, including GSIs.

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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
NOTCH1 A2256fs frameshift unknown NOTCH1 A2256fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2256 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). A2256fs has been identified in the scientific literature (PMID: 25564152), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown.
NOTCH1 P2438fs frameshift unknown NOTCH1 P2438fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2438 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). P2438fs is associated with increased copy number of the NOTCH1 gene in patient tumor samples (PMID: 25564152), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Jun 2020).
NOTCH1 P2462fs frameshift gain of function - predicted NOTCH1 P2462fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2462 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). P2462fs has not been characterized, however, due to the effects of other PEST domain deletions downstream of P2462 (PMID: 16614245, PMID: 16738328), P2462fs is predicted to lead to activation of Notch1 signaling and is associated with increased copy number of the NOTCH1 gene in patient tumor samples (PMID: 25564152).
NOTCH1 Q2444* nonsense gain of function - predicted NOTCH1 Q2444* results in a premature truncation of the Notch1 protein at amino acid 2444 of 2555 (UniProt.org). Q2444* has not been characterized however, due to the effects of other PEST domain truncation mutations (PMID: 25564152, PMID: 15472075, PMID: 28017968), is predicted to lead to a gain of Notch1 protein function.
NOTCH1 Q2487L missense unknown NOTCH1 Q2487L lies within the PEST domain of the Notch1 protein (PMID: 27773930). Q2487L has been identified in the scientific literature (PMID: 25564152), but has not been biochemically characterized and therefore, its effect on Notch1 protein is unknown (PubMed, Sep 2020).
NOTCH1 S2499_F2554del deletion unknown NOTCH1 S2499_F2554del results in the deletion of 56 amino acids in the cytoplasmic domain of the Notch1 protein from amino acids 2499 to 2554 (UniProt.org). S2499_F2554del has been identified in the scientific literature (PMID: 25564152), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Aug 2020).
NOTCH1 S2523L missense unknown NOTCH1 S2523L lies within the cytoplasmic domain of the Notch1 protein (Uniprot.org). S2523L has been identified in the scientific literature (PMID: 25564152), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Aug 2020).
NOTCH1 V1110_S1723del deletion unknown NOTCH1 V1110_S1723del results in the deletion of 614 amino acids in the extracellular domain of the Notch1 protein from amino acids 1110 to 1723 (UniProt.org). V1110_S1723del has been identified in the scientific literature (PMID: 25564152), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Aug 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 S2449fs triple-receptor negative breast cancer sensitive PF-03084014 Preclinical - Pdx Actionable In a preclinical study, PF-03084014 treatment resulted in tumor regression in patient derived xenograft animal models of triple receptor negative breast cancer harboring NOTCH1 S2449fs (PMID: 25564152). 25564152
NOTCH1 mutant triple-receptor negative breast cancer sensitive PF-03084014 Preclinical - Pdx Actionable In a preclinical study, PF-03084014 treatment resulted in tumor regression in patient-derived xenograft models of triple receptor negative breast cancer harboring NOTCH1 mutations (PMID: 25564152). 25564152