Reference Detail

Ref Type

Journal Article

PMID

(24586741)

Authors

Jardim DL, Wheler JJ, Hess K, Tsimberidou AM, Zinner R, Janku F, Subbiah V, Naing A, Piha-Paul SA, Westin SN, Roy-Chowdhuri S, Meric-Bernstam F, Hong DS

Title

FBXW7 mutations in patients with advanced cancers: clinical and molecular characteristics and outcomes with mTOR inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	9	2	2014	e89388	PLoS One

URL

Abstract Text

FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. Clinicopathologic characteristics of cancer patients with FBXW7 mutations and their responses to mTOR inhibitors remain unknown.Using multiplex gene panels we evaluated how the FBXW7 mutation affected the cancer phenotype of patients referred to a phase I clinic starting January 2012. Whenever possible patients positive for FBXW7 mutation were treated with regimens containing an mTOR inhibitors and their outcomes were reviewed.FBXW7 mutations were detected in 17 of 418 patients (4.0%). Among tumor types with more than 10 patients tested, FBXW7 mutations occurred in colorectal cancer (7/49; 14.3%), squamous cell cancer of head and neck (2/18; 11.1%), liver (1/13; 7.7%), and ovarian cancers (1/40; 2.5%). No one clinical, pathological or demographic feature was characteristic of the FBXW7-mutated patient population. The mutation occurred in isolation in only 2/17 (12%) patients, and KRAS was frequently found as a concomitant mutation, especially in patients with colorectal cancer (6/7; 86%). Ten patients were treated on a protocol containing an mTOR inhibitor, with a median time to treatment failure of 2.8 months (range, 1.3-6.8). One patient with liver cancer (fibrolamellar subtype) continues to have a prolonged stable disease for 6.8+ months.In patients with advanced cancers, somatic mutations in FBXW7 usually occur with other simultaneous molecular aberrations, which can contribute to limited therapeutic efficacy of mTOR inhibitors.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach
FBXW7 R479G	mTORC1 Inhibitor
FBXW7 S227A	mTORC1 Inhibitor
FBXW7 R479*	mTORC1 Inhibitor
FBXW7 H468R	mTORC1 Inhibitor
FBXW7 R465C	mTORC1 Inhibitor
FBXW7 R222*	mTORC1 Inhibitor
FBXW7 S462P	mTORC1 Inhibitor
FBXW7 W425R	mTORC1 Inhibitor
FBXW7 G499Vfs*25	mTORC1 Inhibitor
FBXW7 T15_G16insP	mTORC1 Inhibitor
FBXW7 R479L	mTORC1 Inhibitor
FBXW7 R367*	mTORC1 Inhibitor
FBXW7 R479H	mTORC1 Inhibitor
FBXW7 R224*	mTORC1 Inhibitor
FBXW7 I435fs	mTORC1 Inhibitor
FBXW7 H460R	mTORC1 Inhibitor
FBXW7 inact mut	mTORC1 Inhibitor
FBXW7 W486*	mTORC1 Inhibitor
FBXW7 R479Q	mTORC1 Inhibitor
FBXW7 R465P	mTORC1 Inhibitor
FBXW7 G423*	mTORC1 Inhibitor
FBXW7 del	mTORC1 Inhibitor
FBXW7 loss	mTORC1 Inhibitor
FBXW7 R465Y	mTORC1 Inhibitor
FBXW7 R505L	mTORC1 Inhibitor
FBXW7 K299fs	mTORC1 Inhibitor
FBXW7 K11R	mTORC1 Inhibitor
FBXW7 C453fs	mTORC1 Inhibitor
FBXW7 R505C	mTORC1 Inhibitor
FBXW7 S282*	mTORC1 Inhibitor
FBXW7 R473fs	mTORC1 Inhibitor
FBXW7 W244*	mTORC1 Inhibitor
FBXW7 R479P	mTORC1 Inhibitor
FBXW7 Q275*	mTORC1 Inhibitor
FBXW7 R465L	mTORC1 Inhibitor
FBXW7 Q306*	mTORC1 Inhibitor
FBXW7 W237*	mTORC1 Inhibitor
FBXW7 R278*	mTORC1 Inhibitor
FBXW7 R465H	mTORC1 Inhibitor
FBXW7 T165fs	mTORC1 Inhibitor
FBXW7 Q47*	mTORC1 Inhibitor
FBXW7 K444fs	mTORC1 Inhibitor
FBXW7 E369*	mTORC1 Inhibitor
FBXW7 R393*	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
FBXW7	E192A	missense	unknown	FBXW7 E192A does not lie within any known functional domains of the Fbxw7 protein (UniProt.org). E192A has been identified in the scientific literature (PMID: 35346215, PMID: 24586741), but has not been biochemically characterized and therefore, its effect on Fbxw7 protein function is unknown (PubMed, Aug 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FBXW7 E192A	fibrolamellar carcinoma	predicted - sensitive	Sirolimus	Case Reports/Case Series	Actionable	In a Phase I study, Rapamune (sirolimus) resulted in prolonged stable disease in a patient with hepatocellular fibrolamellar carcinoma harboring FBXW7 E192A (PMID: 24586741).	24586741