Reference Detail

Ref Type

Journal Article

PMID

(18787170)

Authors

Mao JH, Kim IJ, Wu D, Climent J, Kang HC, DelRosario R, Balmain A

Title

FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science (New York, N.Y.)	321	5895	2008 Sep 12	1499-502	Science

URL

Abstract Text

The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.

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Molecular Profile	Treatment Approach
FBXW7 T15_G16insP	mTORC1 Inhibitor
FBXW7 R479L	mTORC1 Inhibitor
FBXW7 K444fs	mTORC1 Inhibitor
FBXW7 R473fs	mTORC1 Inhibitor
FBXW7 R479Q	mTORC1 Inhibitor
FBXW7 G423*	mTORC1 Inhibitor
FBXW7 R479H	mTORC1 Inhibitor
FBXW7 H460R	mTORC1 Inhibitor
FBXW7 R505C	mTORC1 Inhibitor
FBXW7 R465H	mTORC1 Inhibitor
FBXW7 S462P	mTORC1 Inhibitor
FBXW7 K299fs	mTORC1 Inhibitor
FBXW7 I435fs	mTORC1 Inhibitor
FBXW7 Q306*	mTORC1 Inhibitor
FBXW7 T165fs	mTORC1 Inhibitor
FBXW7 R367*	mTORC1 Inhibitor
FBXW7 Q275*	mTORC1 Inhibitor
FBXW7 E369*	mTORC1 Inhibitor
FBXW7 H468R	mTORC1 Inhibitor
FBXW7 W244*	mTORC1 Inhibitor
FBXW7 G499Vfs*25	mTORC1 Inhibitor
FBXW7 R465Y	mTORC1 Inhibitor
FBXW7 R479P	mTORC1 Inhibitor
FBXW7 K11R	mTORC1 Inhibitor
FBXW7 inact mut	mTORC1 Inhibitor
FBXW7 R224*	mTORC1 Inhibitor
FBXW7 R465C	mTORC1 Inhibitor
FBXW7 R479*	mTORC1 Inhibitor
FBXW7 R479G	mTORC1 Inhibitor
FBXW7 loss	mTORC1 Inhibitor
FBXW7 W486*	mTORC1 Inhibitor
FBXW7 S282*	mTORC1 Inhibitor
FBXW7 W425R	mTORC1 Inhibitor
FBXW7 R222*	mTORC1 Inhibitor
FBXW7 R393*	mTORC1 Inhibitor
FBXW7 R465L	mTORC1 Inhibitor
FBXW7 R505L	mTORC1 Inhibitor
FBXW7 R465P	mTORC1 Inhibitor
FBXW7 S227A	mTORC1 Inhibitor
FBXW7 C453fs	mTORC1 Inhibitor
FBXW7 R278*	mTORC1 Inhibitor
FBXW7 W237*	mTORC1 Inhibitor
FBXW7 Q47*	mTORC1 Inhibitor
FBXW7 del	mTORC1 Inhibitor

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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FBXW7 inact mut	breast cancer	sensitive	Sirolimus	Preclinical - Cell line xenograft	Actionable	In a preclinical study, breast cancer cells harboring a FBXW7 mutation demonstrated sensitivity to Rapamune (sirolimus) in culture and in cell line xenograft models (PMID: 18787170).	18787170