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 PloS one
Vol 9
Issue 2
Date 2014
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.

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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E192A missense unknown FBXW7 E192A does not lie within any known functional domains of the Fbxw7 protein (UniProt.org). E192A has been identified in sequencing studies (PMID: 24586741, PMID: 26328274), but has not been biochemically characterized and therefore, its effect on Fbxw7 protein function is unknown (PubMed, Nov 2018).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FBXW7 E192A fibrolamellar carcinoma predicted - sensitive Sirolimus Phase I 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