Mutations, detection, drugs and drug resistance to metgenees

Mutation forms of met genethe mutation of the MET gene and tumor occurrence or development there is a causal relationship, these mutation sites include V1110I, H1112Y / R, F1218I, D1246H / V, Y1248H, S1254R and M1268T, in the dispersal of papillomacell carcinoma, meta-mutation frequency of 15%Mutations in MET have also been confirmed in childhood liver cell carcinoma and advanced head and neck cancersremove the activation caused by mutations in met's kinase structure domain, a jump mutation has recently been found in met gene exon 14, which has been found in lung cancer in a variety of forms, including point mutations, missing mutations, insertion mutations, etc., which affect the shearing of the 14th exonThe frequency of the 14th exon jump mutation of the MET gene was 2.6-3.2% in pulmonary adenocarcinoma and 2.6-31.8% in pulmonary sarcoma-like cancerOther types of cancer, such as stomach cancer (7.1%), colorectal cancer (0-9.3%), and glioma (0.4%), have all found the 14-year-long exogenous jump mutation of the MET geneso far, 16 cases of lung cancer with met gene 14 exosome shear mutations have been reported to have been treated with Cabotinib (XL184), showing efficacyHow to detect met gene mutations
If a genetic test shows that the MET gene is amplified by 1.5 times, is it reasonable to recommend the use of coctinib, cabotinib or INC280?what results can be detected to determine whether the MET gene is an active mutation? There's a real need to say hereIf it is the MET gene's No14 exon jump mutation, this through the second generation of sequencing detection sequence information, like white and black words is very clear, there is, no is nobut how can we say that the MET gene is amplified? Is there a possible system error for sequencing?so it is generally believed that the MET gene needs to be amplified at least three times, if it is 1.5 times can not be considered met amplificationOf course, if you have to be sure to do in situ immunofluorescent hybridization (FISH), FISH through the MET gene and chromosome 7 fluorescent probe ratio to determine whether the MET gene is amplification, this test is the gold standard if the second-generation gene test MET amplification 1.5 times, through FISH can prove that MET is amplifying, then it is also indeed amplification, can be used with the corresponding targeted drugs for treatment High levels of MET amplification in non-small cell lung cancer are rare, and the probability of MET/CEP7 greater than 5 is only 0.34% In general, if the MET gene has amplified, then the detection of MET protein through immunohistamy (IHC) should be high, this correspondence is well understood Of course, it is not entirely absolute, such as the amplifying of the MET gene was observed in undifferentiated polymorphic sarcoma, but met proteins are not necessarily highly expressive And interestingly based on MET protein overexpression screening patients using MET inhibitors seems to be ineffective, as detailed later MET's targeted drug metgene amplification often indicates a poor prognosis, and if the MET gene is amplification in stomach cancer, the tumor will show a poor overall survival In breast cancer, patients who receivechemotherapy are often associated with a risk of far-ended metastasis and recurrence if the MET gene is amplification (8%) In glioma, met gene amplification is associated with the aggressiveness of glioma if high levels of MET gene amplification, it often indicates that MET may be the gene mutation that drives tumor development and development, and that high levels of MET amplification are associated with the therapeutic effect of the use of citinib Two patients with gastroesophageal cancer were shown to be met gene amplification, and sensitivity to the treatment of citantitinis was also observed a recent study in France showed that 25 MET gene amplification-positive non-small cell lung cancer (greater than 6 MET copies, regardless of met/CEN7 ratio), these patients were enrolled in the group to receive gramtinib treatment, after 8 weeks can be assessed 18 patients, of which 7 patients were partially resusvial (tumor lesions reduced by more than 30%), 6 patients were stable, and 5 patients were in stable condition Met gene and targeted drug resistance In lung cancer or colorectal cancer, MET gene amplification is considered to be the cause of drug resistance in patients with positive mutation of eGFR gene This drug resistance mechanism is present in 5% to 20% of non-small cell lung cancer patients This resistance can be overcome if both EGFR-targeted drugs and MET-targeted drugs are used MET genes can also be integrated with a variety of genes, based on the emergence of second-generation gene detection technology, we can detect a variety of mutations A lung cancer patient who was resistant to chemotherapy was reported to have detected the HLA-DRB1-MET fusion gene, a fusion protein that was analyzed and recommended for citinib, showing very good therapeutic results for up to 8 months resistance to MET-targeted drugs
MET gene can be used if it is a 14-exon jump mutation, or if it is determined to be met high copy number amplification But resistance due to secondary mutations has been found The first cause of resistance is mutations in the MET protein itself, such as mutations in D1246 or Y1248, where these mutation sites are located in the kinase domain of MET, leading to the continuous activation of met proteins these mutations were first found in cell models, and later in lung cancer with no 14 exon jump mutations or MET amplification mutations, and these lung cancer patients developed resistance with the treatment of cintotrini or INC280, and the detection was found to be d1246 or Y1248 mutations these two mutations are resistant to type I lutosinkinase inhibitors such as clenbutetic and INC280, but the type II MET inhibitor Cabotinib (XL184) is still effective for MET present at these drug-resistant mutation sites, providing ideas for patients with resistance This may also suggest that MET amplification may not be a good idea if the type II inhibitor Cabotinib is used at the outset another met-targeted drug resistance cause is activation of EGFR, and in clinical case, a patient has found that this is true, and this resistance to targeted drugs escapes through MET-to-EGFR If patients with met gene 14 exon jumping mutations are most sensitive to the gramatinib, the L861A mutation of the EGFR gene is present of course we also know that the EGFR target drug resistance reason is met gene amplification, now it seems that cancer cells in the drug resistance in fact a lot of times jump around, just do not rush too quickly, into a split transformation is good, really if it is converted into small cell lung cancer that trouble cell models have also found KRAS gene mutations, BRAF gene mutations, PIK3CA mutations, etc , but these mutations have not been clinically proven Problems with met protein overexpression met protein overexpression can be diagnosed by immune histology, and it seems that MET is overexpressed in many cancers 50% of tumors in non-small cell lung cancer overexpress MET, but in most cases MET overexpression does not seem to mean that the MET gene is active There are several main reasons: many cell lines that express metwithised do not show that MET is active and is not sensitive to MET inhibitors many MET-expressed tumors do not show met phosphate several clinical trials that have been selected by evaluating MET inhibitors, and have shown no effect when selecting patients based on MET expression alone Despite this, MET overexpression is still thought to play an important role in tumor progression, and in many types of cancer, MET overexpression is associated with poor prognosis Studies have reported that more MET high expression was found in brain metastases or far-end lymph nodes This complexity of the MET gene, which involves the specific space and time of tumor progression, has led scientists to propose a "cancer gene expediency", which means that the cancer gene is activated only at certain times and in space, while other times it remains dormant This concept is more brain-burning, no longer too much elaboration, such as you are interested in you can leave a message to participate in the discussion future challenges
has so far described four forms of MET receptor activation: MET gene mutation, HGF autosecretion ring, MET gene amplification, and MET gene fusion these four mutations are low-frequency, but are found in many types of cancer, so the population affected is not a minority All four mutations cause the constituent activation of met receptors, known as kinase domains, but they do not necessarily activate the same downstream signaling pathways a small number of patients who needed attention found that there were two mutation forms of MET at the same time, such as 14 exon jumping mutations with both MET amplification and MET For MET's 14 exon test through the second generation gene sequencing, but for met gene amplification test is very challenging, especially how many times the amplification is considered to be amplification, this is a problem, in principle, the results of second-generation gene testing in patients to participate in clinical trials need to BE FISH verification Many PHASE 2 OR 3 CLINICAL TRIALS OF MET FAIL, PERHAPS BECAUSE THEY CANNOT ACCURATELY IDENTIFY WHICH ARE GENUINE MET-ACTIVATED MUTATIONS another problem is the resistance to MET inhibitors, although some of the drug resistance reasons can be available, such as MET targeted drug resistance is one reason is That EGFR is activated found in an zoology trial that both MET-targeted drugs and EGFR-targeted drugs showed better inhibitory effects on tumors, even if EGFR was not overexpressed Author: Network Source: network