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Frequent 4EBP1 amplification induces synthetic dependence on FGFR signaling in cancer

UID: 10959

Author(s): Mohan, Prathibha*, Pasion, Joyce*, Lailler, Nathalie*, de Stanchina, Elisa*, van den Berg, Anke, Diepstra, Arjan, Ciriello, Giovanni*, Sanghvi, Viraj R.*, Wendel, Hans Guido*, Singh, Kamini* * MSK affiliated

Description
Summary from GEO:

"The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We notice that 4EBP1 gains are genetically linked to gains in neighboring genes including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5’UTR that depends on the 4EBP1-EIF4E activity. In summary, we identify the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer."

Overall design from GEO:

"We performed ribosome footprinting and RNA sequencing on six samples of 293T 4A cells including three untreated samples (DMSO) and three samples that were collected 2 hrs after treatment with Doxycycline (2mg/ml). DMSO treated samples are indicated as CT and Dox treated samples are indicate as Dox."
Subject of Study
Homo sapiens
Subject(s)
Doxycycline
Eukaryotic Initiation Factor-4E
MicroRNAs
Ribosome Profiling
Tumor Suppressor Proteins
Access via GEO


Accession #: GSE197735

Access via BioProject


Accession #: PRJNA811788

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus and BioProject databases provide open access to these files.
Associated Publications
Mohan P, Pasion J, Ciriello G, Lailler N, de Stanchina E, Viale A, van den Berg A, Diepstra A, Wendel H, Sanghvi V, Singh K. Frequent 4EBP1 amplification induces synthetic dependence on FGFR signaling in cancer. Cancers. 2022; 14(10):2397.
Equipment Used
Illumina HiSeq 2500

High throughput sequencing system

Dataset Format(s)
TXT
Dataset Size
540.1 KB (TXT), 1.1 MB (TXT)
Data Catalog Record Updated
2023-10-20