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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of experimental medicine	204	8	2007 Aug 6	1813-24	J Exp Med

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	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
FBXW7	R465C	missense	loss of function	FBXW7 R465C lies within WD repeat 3 of the Fbxw7 protein (UniProt.org). R465C confers a loss of Fbxw7 protein function as demonstrated by a loss of Fbxw7-substrate interaction and impaired substrate degradation by Fbxw7, resulting in sustained Notch1 intracellular domain and Myc expression (PMID: 17646409), impaired degradation of Klf5 (PMID: 28963353), aberrant subnuclear localization relative to wild-type Fbxw7 in culture (PMID: 30510140), and reduced suppression of migration, invasion, and colony formation in culture (PMID: 31161818).
FBXW7	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: 28963353).
FBXW7	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, and therefore, R465P is predicted to lead to a loss of function (PMID: 17646409, PMID: 17909001, PMID: 19340001).
FBXW7	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, and therefore, R465Y is predicted to lead to a loss of function (PMID: 17646409, PMID: 17909001, PMID: 19340001).
FBXW7	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, and therefore, R479G is predicted to lead to a loss of function (PMID: 17646409, PMID: 17575125, PMID: 22608923).
FBXW7	R479Q	missense	loss of function	FBXW7 R479Q lies within WD repeat 3 of the Fbxw7 protein (UniProt.org). R479Q confers a loss of FBXW7-substrate interation and impairs substrate degradation by FBXW7, resulting in sustained Notch1 intracellular domain and Myc expression (PMID: 17646409, PMID: 25450649), and aberrant subcellular nuclear localization and loss of Notch1 intracellular domain binding in culture (PMID: 30510140).
FBXW7	R505C	missense	loss of function	FBXW7 R505C lies within WD repeat 4 of the Fbxw7 protein (UniProt.org). R505C results in ubiquitination and degradation of Braf similar to wild-type Fbxw7 in cultured cells (PMID: 32907612), but confers a loss of function to Fbxw7 as indicated by a loss of binding to NICD in cell culture (PMID: 17646409), impaired degradation of NICD, resulting in increased activity in a luciferase assay (PMID: 27247421), failure to degrade cyclin E, c-Myc, and Mcl1 in cell culture (PMID: 32907612), aberrant subnuclear localization (PMID: 30510140), and impaired degradation of Klf5 in cell culture (PMID: 28963353).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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 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-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 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 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