Trametinib, a drug that inhibits the protein kinase MEK, has been found to increase the lifespan of fruit flies by 10%. If the drug has a similar effect in homo sapiens then it might prolong life by as much as 10 years, causing this discovery to make the international news headlines a few days ago. The work was carried out in the laboratory of Linda Partridge, which is based at University College London and at the Max Planck Institute for Biology of Ageing in Cologne, Germany. The research was published in the June 25th 2015 issue of the journal Cell.
MEK, the protein kinase targeted by Trametinib, was discovered in Philip Cohen's laboratory in the MRC-PPU, Dundee over 25 years ago, while they were studying the mechanism by which Nerve Growth Factor induces the differentiation of neurons. They found that the mitogen-activated protein (MAP) kinases, termed ERK1 and ERK2, were switched on by another kinase in NGF-stimulated cells, which they purified and characterized and termed MAP kinase kinase1-4. The protein kinase was later renamed MEK and shown to be activated by yet another protein kinase called RAF5,6. The Cohen lab subsequently found that neuronal differentiation required the sustained activation of MEK, ERK1 and ERK2, explaining why it was induced by NGF but not by EGF7,8.
Trametinib was developed for clinical use in cancer by GlaxoSmithKline and approved for the treatment of malignant melanoma in 2013. The combination of Trametinib with the Raf inhibitor Dabrafenib later proved to be even more effective and to delay the onset drug resistance considerably and was approved in 2014. These drugs were key components of GlaxoSmithKline's oncology drug portfolio, which they sold last year to Novartis for US$9.1 billion.
The story of Trametinib shows once again the importance of carrying out basic fundamental research on important biological questions, and how it can lead to completely unforeseen consequences over a quarter of a century later.
References
1. Gomez et al, 1991, Nature 353, 170-173; 2. Nakielny et al, 1992, EMBO J. 11, 213-2129; 3.Nakielny et al, 1992, FEBS Lett. 308, 183-189; 4. Ashworth et al, 1992, Oncogene 7, 25555-25556; 5. Howe et al, 1992, Cell 71, 335-342; 6. Kyriakis et al, 1992, Nature 358, 417-421;
7. Traverse et al, 1992, Biochem. J. 288, 351-355; Traverse et al, 1994, Curr. Biol.4, 694-701
MEK, the protein kinase targeted by Trametinib, was discovered in Philip Cohen's laboratory in the MRC-PPU, Dundee over 25 years ago, while they were studying the mechanism by which Nerve Growth Factor induces the differentiation of neurons. They found that the mitogen-activated protein (MAP) kinases, termed ERK1 and ERK2, were switched on by another kinase in NGF-stimulated cells, which they purified and characterized and termed MAP kinase kinase1-4. The protein kinase was later renamed MEK and shown to be activated by yet another protein kinase called RAF5,6. The Cohen lab subsequently found that neuronal differentiation required the sustained activation of MEK, ERK1 and ERK2, explaining why it was induced by NGF but not by EGF7,8.
Trametinib was developed for clinical use in cancer by GlaxoSmithKline and approved for the treatment of malignant melanoma in 2013. The combination of Trametinib with the Raf inhibitor Dabrafenib later proved to be even more effective and to delay the onset drug resistance considerably and was approved in 2014. These drugs were key components of GlaxoSmithKline's oncology drug portfolio, which they sold last year to Novartis for US$9.1 billion.
The story of Trametinib shows once again the importance of carrying out basic fundamental research on important biological questions, and how it can lead to completely unforeseen consequences over a quarter of a century later.
References
1. Gomez et al, 1991, Nature 353, 170-173; 2. Nakielny et al, 1992, EMBO J. 11, 213-2129; 3.Nakielny et al, 1992, FEBS Lett. 308, 183-189; 4. Ashworth et al, 1992, Oncogene 7, 25555-25556; 5. Howe et al, 1992, Cell 71, 335-342; 6. Kyriakis et al, 1992, Nature 358, 417-421;
7. Traverse et al, 1992, Biochem. J. 288, 351-355; Traverse et al, 1994, Curr. Biol.4, 694-701