Year: 2014
Type: article
Abstract: Melanomas are characterized by mutations that lead to constitutive activation of the MAPK pathway, with the BRAFV600E mutation found in around 50% of patients. The advent of drugs such as vemurafenib that target the activated form of BRAF has led to dramatic responses in patients bearing this mutation. Although a few patients exhibit long-term benefits, in the great majority resistance occurs within a median 6 months. Multiple mechanisms of resistance have been described (Lito et al., 2013) including activation of PI3K signalling, alternative splicing of BRAF or constitutive activation of alternative components of the MAPK pathway either upstream of BRAF, such as receptor tyrosine kinases and NRAS, or downstream, such as MEK. The fact that there are so many routes to bypass the effectiveness of anti-BRAF therapy means that following relapse many patients may contain multiple metastases each with differing mechanisms underlying therapeutic resistance. Treating patients with a range of drugs each targeting a different resistance mechanism is not a viable option. Now, a new approach has been revealed by the study of Boussemart et al. (2014). Multiple mechanisms of resistance to anti-BRAF or anti-MEK therapy appear to converge on a key component of the translation initiation machinery. Cap-dependent translation of mRNAs requires they are brought to the ribosome by the eIF4F complex that comprises eIF4E, together with eIF4G, a scaffolding protein, and the RNA helicase eIF4A (Fig. 1). Importantly, eIF4F formation is inhibited by 4EBP1 that binds eIF4E to block its association with eIF4G. Almost all mRNAs require the eIF4F complex for translation (Blagden and Willis, 2011). The exceptions, including the heat shock proteins, ATF4 that responds to ER stress, and Myc, are translated via internal ribosome entry sites in a cap-independent fashion. By developing a method that enabled eIF4E–eIF4G complex formation to be measured in situ, the authors found that vemurafenib treatment of melanoma cell lines increased the levels of inhibitory eIF4E–4EBP1 complex at the expense of the pro-translation eIF4E–eIF4G complex. This reduced translation of polysome-associated mRNAs by up to 30% by 24-h post-treatment. Significantly, the disruption of the eIF4E–eIF4G complex was not observed in some vemurafenib-resistant cell lines. Similar observations were made with dabrafenib and trametinib and combinations of both, and stable eIF4E–eIF4G complexes were also observed in colon cancer cells in which resistance is driven by an activating mutation in PI3K together with EGFR overexpression. Although phosphorylation of 4EBP1 in response to a number of signals, for example by ERK, can prevent it binding and inhibiting eIF4E, the authors identified a different mechanism that promoted the stability of the eIF4E–eIF4G complex; using a combination of comparative gene expression analysis together with siRNA knock-down of candidate genes, they identified BMF (BCL2-Modifying Factor) as a gene whose knock-down led to resistance of a melanoma cell line to vemurafenib. BMF (Pinon et al., 2008) encodes a pro-apoptotic factor, that is upregulated in anoikis and which mediates apoptosis if cap-dependent translation is inhibited by a range of signals including hypoxia, serum-deprivation and inhibition of the PI3K pathway. Indeed, BMF had already been identified by the Aplin laboratory as being implicated in acquired BRAF-inhibitor resistance in melanoma (Shao and Aplin, 2012). Importantly, in some cell lines vemurafenib leads to a strong increase in BMF expression in sensitive, but not resistant cells. Moreover, depletion of BMF decreased vemurafenib's capacity to drive eIF4G cleavage that disrupts the formation of the pro-translation eIF4F complex. Supporting the notion that a stable eIF4E–eIF4G complex promotes vemurafenib resistance, the small molecule 4EG inhibitor-1 that disrupts this complex, or a flavagline inhibitor of eIF4A, decreased survival in vemurafenib-resistant cells, but not sensitive cells and synergized with vemurafenib in killing resistant cells in culture and in xenografts. Similar synergies were also found using other translation inhibitors, but not with chemotherapeutic agents such as doxorubicin, or rapamycin which failed to induce dephosphorylation of 4EBP1 in vemurafenib-resistant cells. In examining patient tumour samples, a decrease in eIF4F complex formation was observed in melanoma samples from responding tumours compared to samples pretherapy, while for all resistant tumours, there was an increase in eIF4F complex formation compared to samples from the same tumours taken prior to therapy. “control of cap-dependent mRNA translation can strongly influence sensitivity to targeted anti-BRAF therapies”
Source: Pigment Cell & Melanoma Research
DOI: 10.1111/pcmr.12314
Authors: Halime Kalkavan, Colin R. Goding
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2029693032