Reference Detail

Ref Type

Journal Article

PMID

(32907612)

Authors

Yeh CH, Bellon M, Wang F, Zhang H, Fu L, Nicot C

Title

Loss of FBXW7-mediated degradation of BRAF elicits resistance to BET inhibitors in adult T cell leukemia cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer	19	1	2020 09 09	139	Mol Cancer

URL

Abstract Text

Human T cell leukemia virus type 1 (HTLV-1)-associated adult T cell leukemia (ATL) has a very poor prognosis with a median survival of 8 months and a 4-year overall survival of 11% for acute ATL. Present treatment options are limited and there is no curative therapy for ATL. Ubiquitin ligase FBXW7 is commonly mutated or functionally inactivated in human cancers. Consistent with the notion that FBXW7 controls the degradation of many oncoproteins, loss of FBXW7 has been linked to increased drug resistance or sensitivity in cancer cells.In this study, we have characterized FBXW7 mutants previously identified in HTLV-I-infected ATL patient samples. TET-inducible ATL cells carrying wild type or mutated FBXW7 were analyzed for target degradation and for drug sensitivity.Our results demonstrate that mutations in FBXW7 can selectively disrupt ubiquitination and proteasome degradation of target proteins: c-MYC, cyclin E and MCL1. Both c-MYC and MYCN were highly expressed in uncultured ATL patient's samples and ATL-derived cell lines; and ATL cells demonstrated sensitivity to BET inhibitors in vitro and in vivo. High-throughput reverse phase protein array revealed BRAF as a novel target of FBXW7 and further experiments showed that mutations in FBXW7 preventing degradation of BRAF provided resistance to BET inhibitors. In contrast to R465, hot spot FBXW7 mutations at R505C retained degradation of BRAF but not NOTCH1, c-MYC, cyclin E, or MCL1. Finally, a combination therapy using BET inhibitors along with a BRAF or an ERK inhibitor prevented tumor cell resistance and growth.Our results suggest that FBXW7 status may play an important role in drug therapy resistance of cancer cells. Genetic characterization of FBXW7 may be one factor included in future personalized cancer treatment identification.

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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	D510E	missense	loss of function	FBXW7 D510E lies within WD repeat 4 of the Fbxw7 protein (UniProt.org). D510E induces degradation of Myc, Mcl-1, Cyclin E (PMID: 27247421) and Braf in culture (PMID: 32907612), but results in loss of binding to Mlst8 (PMID: 34741373), loss of binding and degradation of NICD leading to increased Notch transcriptional activity in a reporter assay, transformation in the context of either the viral protein, Tax, TP53 R276H, or MYC F138C in cultured cells, and increased tumor growth in a transformed mouse model (PMID: 27247421).
FBXW7	D527G	missense	loss of function - predicted	FBXW7 D527G lies within WD repeat 4 of the Fbxw7 protein (UniProt.org). D527G retains the ability to target Myc, Mcl-1, Braf, and Cyclin E for degradation (PMID: 32907612 , PMID: 27247421), binds to the large T antigen of Merkel cell polyomavirus similar to wild-type Fbxw7, and demonstrates increased binding to small T antigen in culture (PMID: 32427880), but results in decreased binding to Mlst8 (PMID: 34741373), fails to bind and degrade NICD in cultured cells leading to increased Notch transcriptional activity in a reporter assay, and results in transformation in the context of the viral protein, Tax, in culture (PMID: 27247421), and therefore, is predicted to lead to a loss of Fbxw7 protein function.
FBXW7	H468R	missense	loss of function	FBXW7 H468R lies within WD repeat 3 of the Fbxw7 protein (UniProt.org). H468R confers a loss of function to the Fbxw7 protein as demonstrated by an inability to induce degradation of cyclin E, c-Myc, Mcl-1, and Braf in cultured cells, and confers resistance to some BET inhibitors in cultured cells (PMID: 32907612), and results in impaired degradation of NICD in cultured cells, potentially leading to increased Notch1 signaling (PMID: 27247421).	Y
FBXW7	L443F	missense	loss of function - predicted	FBXW7 L443F lies within WD repeat 2 of the Fbxw7 protein (UniProt.org). L443F induces degradation of Mcl-1 and Braf similar to wild-type Fbxw7 in culture but fails to induce Cyclin E degradation (PMID: 32907612) and results in a loss of NICD degradation leading to increased Notch transcriptional activity in a reporter assay (PMID: 27247421), and therefore, is predicted to lead to a loss of Fbxw7 protein function.
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).
FBXW7	S462P	missense	loss of function	FBXW7 S462P lies within WD repeat 3 of the Fbxw7 protein (UniProt.org). S462P confers a loss of function to the Fbxw7 protein as demonstrated by an inability to induce degradation of cyclin E, c-Myc, Mcl-1, and Braf in cultured cells, and confers resistance to some BET inhibitors in cultured cells (PMID: 32907612), and results in impaired degradation of NICD in cultured cells, potentially leading to increased Notch1 signaling (PMID: 27247421).	Y
FBXW7	T416A	missense	unknown	FBXW7 T416A lies within WD repeat 1 of the Fbxw7 protein (UniProt.org). T416A retains the ability to bind and degrade NICD (PMID: 27247421, PMID: 32907612), Myc, Mcl-1, Braf, Cyclin E (PMID: 32907612), and Mlst8 in culture (PMID: 34741373), but results in decreased inhibition of Notch transcriptional activity in a reporter assay (PMID: 27247421), and therefore, its effect on Fbxw7 protein function is unknown.
FBXW7	W406R	missense	unknown	FBXW7 W406R lies within WD repeat 1 of the Fbxw7 protein (UniProt.org). W406C retains the ability to bind and degrade NICD (PMID: 27247421, PMID: 32907612), Myc, Mcl-1, Braf, and Cyclin E (PMID: 32907612), binds to the large T antigen of Merkel cell polyomavirus similar to wild-type Fbxw7, and demonstrates increased binding to small T antigen in culture (PMID: 32427880), but results in decreased inhibition of Notch transcriptional activity in a reporter assay (PMID: 27247421), and therefore, its effect on Fbxw7 protein function is unknown.
FBXW7	W425R	missense	loss of function	FBXW7 W425R lies within WD repeat 2 of the Fbxw7 protein (UniProt.org). W425R results in degradation of Mcl1, but confers a loss of function to the Fbxw7 protein as demonstrated by impaired degradation of cyclin E, c-Myc, and Braf in cultured cells (PMID: 32907612) and leads to dimerization with wild-type Fbxw7 in cultured cells, thereby preventing degradation of NICD and potentially resulting in increased Notch signaling (PMID: 27247421), and confers resistance to some BET inhibitors in cultured cells (PMID: 32907612).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FBXW7 positive	adult T-cell leukemia/lymphoma	predicted - sensitive	JQ1	Preclinical - Cell line xenograft	Actionable	In a preclinical study, adult T cell leukemia cells expressing FBXW7 in a mouse model demonstrated decreased tumor volume when treated with JQ1 (PMID: 32907612).	32907612
FBXW7 H468R	adult T-cell leukemia/lymphoma	resistant	JQ1	Preclinical - Cell culture	Actionable	In a preclinical study, adult T cell leukemia cells expressing FBXW7 H468R were resistant to treatment with JQ1 in culture (PMID: 32907612).	32907612
FBXW7 H468R	adult T-cell leukemia/lymphoma	resistant	Birabresib	Preclinical - Cell culture	Actionable	In a preclinical study, adult T cell leukemia cells expressing FBXW7 H468R were resistant to treatment with Birabresib (OTX015) in culture (PMID: 32907612).	32907612
FBXW7 S462P	adult T-cell leukemia/lymphoma	resistant	Birabresib	Preclinical - Cell culture	Actionable	In a preclinical study, adult T cell leukemia cells expressing FBXW7 S462P were resistant to treatment with Birabresib (OTX015) in culture (PMID: 32907612).	32907612
FBXW7 S462P	adult T-cell leukemia/lymphoma	sensitive	JQ1 + PLX8394	Preclinical - Cell culture	Actionable	In a preclinical study, the combination treatment of JQ1 and PLX8394 resulted in greater decreased proliferation of adult T cell leukemia cells expressing FBXW7 S462P when compared to treatment with JQ1 alone in culture (PMID: 32907612).	32907612
FBXW7 S462P	adult T-cell leukemia/lymphoma	sensitive	JQ1 + Ulixertinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination treatment of JQ1 and Ulixertinib (BVD-523) resulted in greater decreased proliferation of adult T cell leukemia cells expressing FBXW7 S462P when compared to treatment with JQ1 alone in culture (PMID: 32907612).	32907612
FBXW7 S462P	adult T-cell leukemia/lymphoma	resistant	JQ1	Preclinical - Cell culture	Actionable	In a preclinical study, adult T cell leukemia cells expressing FBXW7 S462P treated with JQ1 demonstrated resistance in both short term and long term culture, and showed increased phosphorylation of Braf, Mek, and Erk, and increased expression of Stat3 and Myc (PMID: 32907612).	32907612
FBXW7 W425R	adult T-cell leukemia/lymphoma	resistant	JQ1	Preclinical - Cell culture	Actionable	In a preclinical study, adult T cell leukemia cells expressing FBXW7 W425R demonstrated resistance to treatment with JQ1 in culture (PMID: 32907612).	32907612
FBXW7 W425R	adult T-cell leukemia/lymphoma	resistant	Birabresib	Preclinical - Cell culture	Actionable	In a preclinical study, adult T cell leukemia cells expressing FBXW7 W425R demonstrated resistance to treatment with Birabresib (OTX015) in culture (PMID: 32907612).	32907612