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Cancer Discov. 2018 Oct 10. pii: CD-18-0606. doi: 10.1158/2159-8290.CD-18-0606. [Epub ahead of print]

EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center.
2
Tri-Institutional Program for Computational Biology and Medicine, Memorial Sloan Kettering Cancer Center.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center.
4
Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center.
5
Department of Pharmacology, Weill Cornell Medicine.
6
Human Oncology and Pathogenesis, Memorial Sloan Kettering Cancer Center.
7
Pathology, Memorial Sloan Kettering Cancer Center.
8
Computational Biology Program, Memorial Sloan Kettering Cancer Center.
9
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center faginj@mskcc.org.

Abstract

Translation initiation is orchestrated by the cap binding and 43S pre-initiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX is enriched in advanced thyroid cancers, where it displays a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113spl variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113spl. ATF4 and c-MYC induce expression of aminoacid transporters and enhance sensitivity of mTOR to aminoacid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4 and mTOR kinase inhibitors.

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