3.3.4 RAS-RAF-MAPK signal pathway abnormal RAS family including KRAS, NRAS and HRAS, belonging to GTP binding protein, with GTPase activity. KRAS mutations are found in approximately 25% of lung adenocarcinomas and 5% of squamous cell carcinomas, more common in smokers.47 However, there are no potent inhibitors of RAS mutation sites. RAS downstream signal target BRAF mutations are more common in people with a history of smoking, the mutation rate in lung adenocarcinoma of about 6% in lung squamous cell carcinoma mutation rate of about 4%, common mutations include V600E, D594G, L596R, G465V, etc. [48- 49] BRAF gene can encode serine / threonine protein kinase, through phosphorylation of MEK and activation of downstream ERK signal pathway mediation tumor development. Current BRAF inhibitors are dabrafenib and vemurafenib. In Phase I / II studies, patients with NSCLC who underwent treatment of BRAF V600E mutations with darlafinide had an ORR of 54% and a longest remission lasting 49 weeks and were well tolerated [50]. Another included In a clinical study of 78 patients with BRAFV600E mutant NSCLC, the overall response rate (ORR) was 32% for Dabrafenib monotherapy; in a randomized study, oral MEK inhibitor selumetinib Chemotherapy for the treatment of KRAS mutations in patients with non-small cell lung cancer, compared with chemotherapy alone, patients with increased efficiency, PFS extended [51].
3.3.5 RET translocation The RET receptor, encoded by the proto-oncogene c-ret, is a tyrosine kinase receptor that includes the extracellular domain, the transmembrane domain, and the intracellular domain. The major ligands of RET protein are glial cell line-derived neurotrophic factor (GDNF) family, including GDNF, neurturin and persephin.RET receptors are part of the cell surface complexes, which interact with the GDNF family Lt; RTI ID = 0.0 & gt; of GDNF & lt; / RTI & gt; family members. RET receptor binding to the ligand, through the formation of RET-homodimer and activation of kinase domain, resulting in intracellular domain autophosphorylation, and then activate the RAS / RAF / MEK / ERK, PI3K / AKT, JNK and other signals path.
The RET gene can be fused with genes such as CCDC6, KIF5B, NCOA4, and TRIM33, and is approximately 1% in patients with lung adenocarcinoma [52-54]. In younger, non-smokers, RET mutations 7% to 17%. [54] Current clinical RET inhibitors include Cabozantinib, Vandetanib, Sunitinib, Ponatinib and Regorafenib.
3.4 Immunotherapy
In recent years, with the understanding of tumor immune response and immune evasion mechanism deepening, new immunotherapy methods continue to appear, such as tumor vaccines, monoclonal antibodies. Melanoma-associated antigen vaccine, BLP25 liposome vaccine, TG4010 vaccine, Belagenpumatucel-L, CimaVax-EGF vaccine and other drugs in the early clinical study confirmed effective. Recently, a series of Phase II / III clinical studies have confirmed that immunodepressin inhibitor drugs such as Programmed death-1 (PD-1) / Programmed death ligand-1 (PD-L1) antibodies such as nivolumab, pembrolizumab, MPDL3280A and CTLA- 4 (cytotoxic tlymphocyte antigen 4) inhibitors, such as ipilimumab, have good efficacy for NSCLC and improve survival in patients [55-58]. The presence of these agents appears to be resistant to multicellular resistance Patients who are genetically engineered for mutation provide a new therapeutic option.
4 Outlook
New targeted therapies and the emergence of immunotherapeutic drugs have provided more options for the treatment of lung cancers, particularly NSCLC, but have also posed greater challenges, such as how to interpret many Phase I – III clinical How to choose the appropriate treatment strategy, in order to maximize the survival of patients and improve the quality of life, these problems are waiting for the treatment of patients with acute pancreatitis, We continue to explore and summarize the clinical work.
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