Reference Detail

Ref Type Journal Article
PMID (17646409)
Authors O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, Hardwick J, Welcker M, Meijerink JP, Pieters R, Draetta G, Sears R, Clurman BE, Look AT
Title FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.
Journal The Journal of experimental medicine
Vol 204
Issue 8
Date 2007 Aug 6
URL
Abstract Text gamma-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
R465C missense loss of function FBXW7 R465C lies within the WD 3 repeat region of the Fbxw7 protein (UniProt.org). R465C confers a loss of FBXW7-substrate interaction and impairs substrate degradation by FBXW7, resulting in sustained NICD and MYC expression (PMID: 17646409) and also has impaired degradation of Klf5 (PMID: 2896335).
R465H missense loss of function FBXW7 R465H (corresponds to R385H in isoform 2) lies within the WD repeat 3 of the Fbxw7 protein (UniProt.org). R465H confers a loss of FBXW7-substrate interaction and impairs substrate degradation by FBXW7, resulting in sustained NICD and MYC expression (PMID: 17646409) and also has impaired degradation of Klf5 (PMID: 2896335).
R465P missense loss of function - predicted FBXW7 R465P lies within the WD repeat domain of the Fbxw7 protein (UniProt.org). R465P has not been characterized, however other R465 hotspots inactivate Fbxw7, therefore, R465P is predicted to lead to a loss of function (PMID: 17646409, PMID: 17909001, PMID: 19340001).
R465Y missense loss of function - predicted FBXW7 R465Y lies within the WD repeat domain of the Fbxw7 protein (UniProt.org). R465Y has not been characterized however other R465 hotspots inactivate Fbxw7 therefore, R465Y is predicted to lead to a loss of function (PMID: 17646409, PMID: 17909001, PMID: 19340001).
R479G missense loss of function - predicted FBXW7 R479G lies within the WD repeat domain of the Fbxw7 protein (UniProt.org). R479G has not been characterized, however other R479 hotspot mutations inactivate Fbxw7 therefore, R479G is predicted to lead to a loss of function (PMID: 17646409, PMID: 17575125, PMID: 22608923).
R479P missense loss of function - predicted FBXW7 R479P lies within the WD repeat domain of the Fbxw7 protein (UniProt.org). R479P has not been characterized, however other R479 hotspot mutations inactivate Fbxw7 therefore, R479P is predicted to lead to a loss of function (PMID: 17646409, PMID: 17575125, PMID: 22608923).
R479Q missense loss of function FBXW7 R479Q lies within the WD 3 repeat region of the Fbxw7 protein (UniProt.org). R479Q confers a loss of FBXW7-substrate interation and impairs substrate degradation by FBXW7, resulting in sustained NICD and MYC expression (PMID: 17646409, PMID: 25450649).
R505C missense loss of function FBXW7 R505C lies within the WD 4 repeat region of the Fbxw7 protein (UniProt.org). R505C confers a loss of FBXW7-substrate interation and impairs substrate degradation by FBXW7, resulting in sustained NICD and MYC expression (PMID: 17646409) and also has impaired degradation of Klf5 (PMID: 2896335).
R505L missense loss of function FBXW7 R505L lies within the WD repeat 4 of the Fbxw7 protein (UniProt.org). R505L confers a loss of function on Fbxw7, as demonstrated by activation of the NOTCH pathway in cultured cells (PMID: 17646409) and the inability to bind substrates (PMID: 28522751).
A2441fs frameshift unknown NOTCH1 A2441fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2441 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). A2441fs has not been characterized individually, however, cells harboring both A2441fs and L1574P demonstrated constitutive Notch signaling in culture (PMID: 17646409).
E1583_Q1584insPVELMPPE insertion unknown NOTCH1 E1583_Q1584insPVELMPPE results in the insertion of eight amino acids in the extracellular domain of the Notch1 protein between amino acids 1583 and 1584 (UniProt.org). E1583_Q1584insPVELMPPE has not been characterized in the scientific literature and therefore, its effect on Notch1 protein function is unknown (PubMed, Jul 2018).
H2428fs frameshift gain of function - predicted NOTCH1 H2428fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2428 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). H2428fs is predicted to confer a gain of function to the Notch1 protein, as demonstrated by stabilization of the NOTCH intracellular domain and activation of the NOTCH pathway (PMID: 17646409).
P2475fs frameshift gain of function - predicted NOTCH1 P2475fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2475 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). P2475fs is predicted to confer a gain of function to the Notch1 protein, as demonstrated by stabilization of the Notch intracellular domain and activation of the Notch pathway (PMID: 17646409).
P2493fs frameshift unknown NOTCH1 P2493fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2493 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). P2493fs has not been characterized individually however, cells harboring both P2493fs (reported as P2493fs*100) and L1574P demonstrated constitutive Notch signaling in culture (PMID: 17646409), and therefore its effect on Notch1 protein function is unknown (PubMed, Sep 2018).
P2514* nonsense unknown NOTCH1 P2514* results in a premature truncation of the Notch1 protein at aa 2514 of 2555 (UniProt.org). P2514* has not been characterized individually and therefore its effect on Notch1 protein function unknown (PubMed, Sep 2018), however, cells harboring both P2514* and L1600P demonstrated constitutive Notch signaling in culture (PMID: 17646409).
P2514fs frameshift unknown NOTCH1 P2514fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2514 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). P2514fs has not been characterized individually and therefore its effect on Notch1 protein function is unknown (PubMed, Sep 2018), however, cells harboring both P2514fs and L1600P demonstrated constitutive Notch signaling in culture (PMID: 17646409).
V2443fs frameshift unknown NOTCH1 V2443fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2443 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). V2443fs has not been characterized individually however, cells harboring both V2443fs (reported as V2443fs*34) and L1593P demonstrated constitutive Notch signaling in culture (PMID: 17646409) and therefore, the effect of V2443fs on Notch1 protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FBXW7 del T-cell adult acute lymphocytic leukemia resistant MRK-003 Preclinical Actionable In a preclinical study, homozygous deletion of FBXW7 is conferred resistance to gamma secretase inhibitor, MRK-003, by activation of the NOTCH pathway and stablization of MYC as demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cell lines (PMID: 17646409). 17646409
FBXW7 R505L T-cell adult acute lymphocytic leukemia resistant MRK-003 Preclinical Actionable In a preclinical study, FBXW7 R505L may conferred resistance to gamma secretase inhibitor, MRK-003, by activation of the NOTCH pathway and stablization of MYC as demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cell lines (PMID: 17646409). 17646409
FBXW7 R505C T-cell adult acute lymphocytic leukemia resistant MRK-003 Preclinical Actionable In a preclinical study, FBXW7 R505C conferred resistance to gamma secretase inhibitor, MRK-300, by activation of the NOTCH pathway and stablization of MYC as demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cell lines (PMID: 17646409). 17646409
FBXW7 R465H T-cell adult acute lymphocytic leukemia resistant MRK-003 Preclinical Actionable In a preclinical study, FBXW7 R465H conferred resistance to gamma secretase inhibitor, MRK-003, by activation of the NOTCH pathway and stablization of MYC as demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cell lines (PMID: 17646409). 17646409
FBXW7 R465C T-cell adult acute lymphocytic leukemia resistant MRK-003 Preclinical Actionable In a preclinical study, FBXW7 R465C conferred resistance to gamma secretase inhibitor, MRK-003, by activation of the NOTCH pathway and stablization of MYC as demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cell lines (PMID: 17646409). 17646409
FBXW7 R479Q T-cell adult acute lymphocytic leukemia resistant MRK-003 Preclinical Actionable In a preclinical study, FBXW7 R479Q conferred resistance to gamma secretase inhibitor, MRK-003, by activation of the NOTCH pathway and stablization of MYC as demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cell lines (PMID: 17646409). 17646409