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Updated: Sep 21, 2025

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Published on: January 7, 2019

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Frequent 4EBP1 Amplification Induces Synthetic Dependence on FGFR Signaling in Cancer

Prathibha Mohan1, Joyce Pasion1, Giovanni Ciriello2

  • 1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Cancers
|May 28, 2022
PubMed

Insights

Genomic gains in breast and lung cancer target FGFR1, not 4EBP1, attenuating 4EBP1

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The translation initiation factor eIF4E is oncogenic, while its inhibitor, 4EBP1, acts as a tumor suppressor.
  • The precise molecular mechanisms of 4EBP1 in cancer remain unclear.
  • Genomic copy number gains at Chr. 8p11, including 4EBP1, are observed in breast and lung cancers.

Purpose of the Study:

  • To elucidate the molecular effects of 4EBP1 activation in cancer.
  • To investigate the genetic targets of Chr. 8p11 gains and their impact on 4EBP1 function.
  • To identify therapeutic vulnerabilities associated with these genetic alterations.

Main Methods:

  • Analysis of genomic copy number gains linked to 4EBP1.
  • Investigating the interaction between FGFR1 gains and 4EBP1 phosphorylation.
  • Utilizing ribosome profiling to identify 4EBP1 translational targets.

Main Results:

  • FGFR1 gains attenuate 4EBP1 function through PI3K-mediated phosphorylation.
  • FGFR1, not 4EBP1, is identified as the primary genetic target of Chr. 8p11 gains.
  • Tumors with these gains exhibit sensitivity to FGFR1 and PI3K inhibition.
  • Ribosome profiling identified key translational targets of 4EBP1, including genes in insulin signaling and metabolism.

Conclusions:

  • Chr. 8p11 gains in breast and lung cancer primarily target FGFR1, leading to suppressed 4EBP1 tumor-suppressive activity.
  • Restoring 4EBP1 function via FGFR1 and PI3K inhibition presents a therapeutic strategy.
  • Understanding 4EBP1's translational targets provides insights into its tumor suppressor role in cancer.
Keywords:
4EBP1FGFR1breast cancereIF4Elung cancerribosome footprinting

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