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Mechanistic target of rapamycin

Jul 21st, 2022 at 10:30   Phones & Tablets   Samālūţ   10 views Reference: 457

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The mechanisms that regulate organismal growth and coordinate it with the availability of nutrients were unknown until a few decades ago. We now know that one pathway—the mechanistic target of rapamycin (mTOR) pathway—is the major nutrient-sensitive regulator of growth in animals and plays a central role in physiology, metabolism, the aging process, and common diseases. This work describes the development of the mTOR field, from its origins in studies into the mechanism of action of the drug rapamycin to our increasingly sophisticated understanding of how nutrients are sensed.

About half of all melanomas have changes (mutations) in the BRAF gene. Melanoma cells with these changes make an altered BRAF protein that helps them grow. Some drugs target this and related proteins, such as the MEK proteins.

If you have melanoma that has spread beyond the skin, a biopsy sample of it will likely be tested to see if the cancer cells have a BRAF mutation. Drugs that target the BRAF protein (BRAF inhibitors) or the MEK proteins (MEK inhibitors) aren’t likely to work on melanomas that have a normal BRAF gene.

Most often, if a person has a BRAF mutation and needs targeted therapy, they will get both a BRAF inhibitor and a MEK inhibitor, as combining these drugs often works better than either one alone.

Histone deacetylases (HDACs) are the group of enzymes that remove the acetyl group from lysine residue. To date, 18 mammalian HDACs have been identified and are characterized into four classes: class I HDACs (HDACs 1, 2, 3, and 8), class II HDACs (HDACs 4, 5, 6, 7, 9, and 10), class IV (HDAC 11) and class III (sirtuin family: sirt1-sirt7). Class II HDACs are further divided into two subgroups: class IIa, which has a large C-terminus, and class IIb, which has two deacetylase domains. Class I, II, and IV HDACs need a zinc ion (Zn2+) and share a similar catalytic core for acetyl-lysine hydrolysis, while class III HDACs require a nicotinamide adenine dinucleotide for their enzyme activity.

Treatment of advanced stage lung cancer is changing rapidly. With the new found knowledge on molecular targets such as the epidermal growth factor receptor (EGFR), effective therapy is now available in a selected population with the target mutation. Single-agent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for patients with activating-EGFR mutation such as base-pair deletion in exon 19 or point mutation at exon 21. At the same time, this class of drugs may be combined with chemotherapy. Studies on the concurrent combination of chemotherapy and EGFR-TKI confirmed a lack of efficacy. A phase II study on sequential intercalated combination has demonstrated an improvement in progression-free survival (PFS), but this needs to be validated by the ongoing phase III study. The third approach is to combine EGFR-TKI as maintenance therapy after tumour response or stable disease to cytotoxic chemotherapy. Two phase III studies have shown improvement in PFS, but the use of biomarkers for the selection of maintenance therapy remains debatable. Cetuximab is a monoclonal antibody against EGFR and its combination with chemotherapy was shown to improve overall survival in an unselected population. A new biomarker using the H-score will help to select patients for this combination.

CDK4/6 inhibitors are a class of medicines used to treat certain types of metastatic breast cancer, which is cancer that has spread to other parts of the body, such as the bones or liver.
CDK4/6 inhibitors are a newer class of medicines used to treat certain types of metastatic breast cancer, which is cancer that has spread to other parts of the body, such as the bones or liver. These medicines interrupt the process through which breast cancer cells divide and multiply. To do this, they target specific proteins known as the cyclin-dependent kinases 4 and 6, abbreviated as CDK4/6. That's why you may hear them referred to as “targeted therapies.” If a breast cancer is hormone-receptor-positive, it means the cancer’s growth is fueled by the hormones estrogen, progesterone, or both. HER2-negative cancers have tested negative for a protein called human epidermal growth factor receptor 2, or HER2, which promotes cancer cell growth. So HER2-negative cancers don’t respond to treatments that target the HER2 protein (such as Herceptin). More than two out of every three breast cancers are both hormone-receptor-positive and HER2-negative. 1 Currently there are three CDK4/6 inhibitors used to treat metastatic breast cancer: