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

Denis L Jardim1, Jennifer J Wheler1, Kenneth Hess2

  • 1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Plos One
|March 4, 2014
PubMed
Abstract

Insights

FBXW7 mutations in advanced cancers are uncommon but often co-occur with other genetic changes. This can limit the effectiveness of mTOR inhibitors, impacting patient treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • FBXW7 is a tumor suppressor gene critical for degrading oncogenic proteins.
  • Preclinical studies indicate FBXW7 mutations may sensitize cancer cells to mTOR inhibitors.

Purpose of the Study:

  • To investigate the clinicopathologic characteristics of cancer patients with FBXW7 mutations.
  • To evaluate the response of FBXW7-mutated cancers to mTOR inhibitor therapy.

Main Methods:

  • Multiplex gene panels were used to identify FBXW7 mutations in patients at a phase I clinic.
  • Outcomes were reviewed for patients with FBXW7 mutations treated with mTOR inhibitors.

Main Results:

  • FBXW7 mutations were found in 4.0% of 418 patients, notably in colorectal and head and neck cancers.
  • FBXW7 mutations frequently occurred with concomitant mutations, particularly KRAS in colorectal cancer.
  • Ten patients received mTOR inhibitors, with a median treatment failure time of 2.8 months.

Conclusions:

  • Somatic FBXW7 mutations in advanced cancers are often accompanied by other molecular alterations.
  • These co-occurring mutations may contribute to the limited efficacy of mTOR inhibitors in this patient group.

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