EGFR mutation T790M
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| Surname | EGFR mutation T790M |
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The EGFR-T790M mutation of the epidermal growth factor receptor ( English Epidermal Growth Factor Receptor ) was discovered as the cause of an acquired resistance of lung adenocarcinomas to Gefitinib or Erlotinib . It is a single missense mutation , a point mutation that causes a different amino acid to be incorporated into a protein . The "missense" mutation is a "meaning-changing" mutation that codes for a different amino acid. In the case of EGFR, a mutation in exon 20 replaces a threonine (T) with a methionine (M) at position 790 in the kinase domain. Threonine is a small polar amino acid; Methionine is a larger non-polar amino acid.
Basics
Tyrosine kinases are a group of enzymes from the protein kinase family , whose task is the reversible transfer of a phosphate group to the hydroxy group of the amino acid tyrosine of another protein. This significantly influences the activity of the target protein.
However, dysregulated tyrosine kinases often play a key role in the development of tumor diseases. In some cancer cells, many of these growth receptors are located on the cell membrane, and the tyrosine kinase is often permanently active in tumor cells. The cell receives the signal to divide without interruption. A tyrosine kinase inhibitor (TKI) can specifically inhibit this tyrosine kinase in order to treat a tumor disease with it, i.e. to slow down the division of cancer cells. This tiny molecule ( English small molecule ) can penetrate through the cell wall into the cell, where the inner part of the receptor occupy, so that the signal chain that leads to cell division, is interrupted. This greatly slows cell growth. Tyrosine kinase inhibitors have a much more specific effect and usually have a lower spectrum of side effects than conventional cytostatics .
1st generation tyrosine kinase inhibitors were developed in the 1990s, followed by 2nd generation tyrosine kinase inhibitors. 3rd generation TKIs are a new class of active ingredients that bind covalently to the EGFR and can overcome resistance to 1st and 2nd generation TKIs in the presence of a T790M mutation.
Clinical significance
Patients with EGFR sensitizing mutations treated with 1st or 2nd generation TKIs should be tested for T790M at the time of clinical or radiographic progression. The results should guide treatment decisions. Tests for the presence of EGFR T790M as a resistance mechanism can either preferably of circulating tumor DNA ( English Circulating free DNA , cfDNA) from plasma by means of the Liquid Biopsy or from the DNA from the tissue by means of conventional biopsy be performed.
A positive T790M result from a cfDNA test may be an indication for therapy targeting the T790M mutation. A tissue biopsy can follow if the Liquid Biopsy for T790M is negative.
The T790M mutation at the exon 20 of the EGFR gene is the most common (primary or acquired) resistance mutation in non small cell lung cancer ( English non small cell lung cancer , NSCLC). Irreversible EGFR inhibitors are characterized by additional strong noncovalent binding motifs and thus have a high potency towards the cysteine ‐ mutated L858R / T790M / C797S EGFR enzyme.
In November 2015, the US Food and Drug Administration (FDA) granted accelerated approval of osimertinib (Tagrisso ® ) for the treatment of patients with advanced lung cancer with activating EGFR mutations. The European Commission followed suit with its approval. The drug has been approved in Germany since February 2016, and as a first-line therapeutic since June 7, 2018.
In order for the T790M test to meet the high quality requirements aimed at, the German Society for Pathology (DGP) and the Federal Association of German Pathologists each carried out a round robin test in 2016 and 2017 as part of the Pathology Quality Assurance Initiative (QuIP).
Individual evidence
- ↑ a b William Pao, Vincent A Miller a. a .: Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain. In: PLoS Medicine. 2, 2005, p. E73, doi : 10.1371 / journal.pmed.0020073 .
- ^ A b Doriano Fabbro, Frank McCormick: Protein Tyrosine Kinases: From Inhibitors to Useful Drugs. Cancer Drug Discovery and Development. Springer Science & Business Media, 2007. ISBN 978-1-59259-962-2 . P. 1ff.
- ↑ DA Cross, SE Ashton et al. a .: AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. In: Cancer Discovery . Volume 4, number 9, September 2014, pp. 1046-1061, doi : 10.1158 / 2159-8290.CD-14-0337 , PMID 24893891 , PMC 4315625 (free full text).
- ↑ T. Stockley, CA Souza, et. al .: Evidence-based best practices for EGFR T790M testing in lung cancer in Canada. In: Current Oncology . 25, 2018, p. 163, doi : 10.3747 / co.25.4044 .
- ↑ Marcel Günther, Michael Juchum, Gerhard Kelter, Heiner Fiebig, Stefan Laufer: Lung cancer: EGFR inhibitors with high effectiveness against the therapy-resistant L858R / T790M / C797S mutant. In: Angewandte Chemie. 128, 2016, p. 11050, doi : 10.1002 / anie.201603736 .
- ↑ Tagrisso: Procedural steps taken and scientific information after the authorization , European Medicines Agency, accessed on February 28, 2019.
- ↑ Benefit assessment procedure for the active ingredient osimertinib (new area of application: non-small cell lung cancer, first-line therapy) , Federal Joint Committee , January 17, 12019. Accessed on February 26, 2019.
- ↑ EGFR mutation analysis, 2017 , Quality Initiative Pathology. Retrieved March 5, 2019.
