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eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies

Lise Boussemart, Hélène Malka-Mahieu, Isabelle Girault, Delphine Allard, Oskar Hemmingsson, Gorana Tomasic, Marina Thomas, Christine Basmadjian, Nigel Ribeiro, Frédéric Thuaud, Christina Mateus, Emilie Routier, Nyam Kamsu-Kom, Sandrine Agoussi, Alexander

Nature 513, 105–109 (04 September 2014) doi:10.1038/nature13572

Editorial comment by professor Reinhard G. Dummer:
A French research group headed by Dr. Vagner has investigated molecular alterations associated drug resistance in V600E mutated tumor cells treated with targeted therapies. The eIF4F translation initiation complex was identified as  a central intersection node  to generate resistance against B raf inhibitors. and MEK inhibitors as well as the combination of both. This complex, that is a key regulator of mRNA translation, is a central mechanism of resistance in melanoma and also in other cancer types such as colon and thyroid cancers. Interestingly, an in-situ test system was developed to demonstrate the functioning of this pathway in human tumor tissue.

Summary

In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS–RAF–MEK–ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K–AKT–mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade1, 2, 3. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m7G) at the 5′ end of messenger RNA, thereby modulating the translation of specific mRNAs4, 5. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E–eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E–eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.

 

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2. Shi, H. et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 4, 80 (2014)

3. Tentori, L., Lacal, P. M. & Graziani, G. Challenging resistance mechanisms to therapies for metastatic melanoma. Trends Pharmacol. Sci. 34, 656–666 (2013)

4. Blagden, S. P. & Willis, A. E. The biological and therapeutic relevance of mRNA translation in cancer. Nature Rev. Clin. Oncol. 8, 280–291 (2011)

5. Silvera, D., Formenti, S. C. & Schneider, R. J. Translational control in cancer. Nature Rev. Cancer 10, 254–266 (2010)