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Kinase convergence on eIF4F

Researchers in France have shown that resistance to BRAF and MEK inhibitors in melanoma and possibly other cancers can be driven by pathways that converge on the eukaryotic translation initiation factor 4F complex.1 The findings suggest developing inhibitors of the complex in combination with marketed kinase inhibitor drugs could help circumvent resistance.

For the few biotechs already developing cancer compounds that disrupt eukaryotic translation initiation factor 4F (eIF4F), such as Egenix Inc. and Isis Pharmaceuticals Inc., the reported data suggest their candidates could have broader utility than previously realized.

eIF4F is a key complex that enables mRNA translation. It is comprised of the eIF4A RNA helicase, the eIF4E cap-binding protein and the eIF4G scaffolding protein. eIF4E binding to eIF4G promotes the assembly of the eIF4F complex, which leads to increased mRNA translation. All three components of the complex have previously been linked to the development or progression of various cancers, and disruption of their activity has been shown to have anticancer effects.2,3

Egenix is developing small molecules for cancer that inhibit the interaction between eIF4E and eIF4G. The biotech plans to select its lead candidate within a year. Isis' antisense oligonucleotide ISIS-EIF4ERx targets eIF4E and is in Phase I/II testing to treat non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer (CRPC).

Now, a group co-led by Stéphan Vagner has published data in Nature showing that the eIF4F complex also acts as a nexus for resistance to BRAF

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