20.04.2022, 02:36
MEK Inhibitor Mechanism of Action, Side Effects, and Uses
Metastatic melanoma is a deadly cancer for which conventional chemotherapy provides little benefit. However, newer therapies involving a pathway called the mitogen-activated protein kinase (MAPK) pathway have demonstrated success in inducing remission.
The MAPK pathway is more accurately termed the RAS-RAF-MEK-ERK pathway, and involves the regulation of cell proliferation and survival. It is constitutionally overactive in 30% of cancers. Two enzymes in this pathway, namely, BRAF and MEK, are target kinases which play crucial roles in the cell cycle.
The first therapies to target this pathway were BRAF inhibitors, but intrinsic and acquired tumor resistance quickly led to treatment failure by reactivation of the MAPK pathway. MEK inhibitors have emerged to partially overcome these resistance mechanisms and are now used in combination with BRAF inhibitors to extend the time to resistance.
MEK is a dual specificity threonine/tyrosine kinase, so called from the term MAPK/ERK kinase. It is a key effector of the three-layered RAS/RAF/MEK/ERK signaling cascade, expressed by seven genes from MAPK1 to MAPK7.
MEK inhibitors bind to and inhibit MEK, inhibiting MEK-dependent cell signaling. This inhibition leads to cell death and the inhibition of tumor growth. These are allosteric binding inhibitors of MEK which inhibit either MEK1 alone, or both MEK1 and MEK2.
What is the mechanism of action of MEK inhibitors?
The MAPK pathway is an intracellular signaling cascade that is involved in the proliferation and survival of tumor cells. Many mutations cause cancer development by activating this pathway, including BRAF and NRAS mutations. MEK is a downstream protein kinase which can be targeted to prevent reactivation of the MAPK pathway in the presence of BRAF or RAS mutations.
Normally, ERK1/2 activation initiates a variety of cellular and nuclear pathways, while also inhibiting Raf activity by a feedback loop to modulate the activity of the MAPK pathway. MEK1/2 inhibition inactivates ERK1/2 and also removes the feedback inhibition on Raf.
Drugs which selectively inhibit the MEK enzymes are able to inhibit growth and to induce the death of cells in the presence of these mutations.
Thus, MEK1/2 is highly selective in inactivating ERK1/2 but leaves other signaling pathways intact. In addition, the non-ATP binding site means they do not typically need to compete with ATP, which is present in very large amounts inside cells. A new ATP-competitive inhibitor has also been designed which is effective in mutants that display drug resistance to the ATP-noncompetitive inhibitors.
The advantages of using combination MEK inhibitor therapy with a BRAF inhibitor is the increased progression-free survival and lower toxicity, when compared with the latter alone.
What are the side effects of MEK inhibitors?
Adverse reactions with MEK inhibitors occur in two stages: immediate (within days of initiation of therapy) and chronic (following several months of exposure). Mild toxicities need not interrupt the treatment, but moderate to severe adverse effects may require temporary withdrawal of the drugs and re-initiation following resolution of the reaction. Such cessation of treatment for short periods does not seem to affect outcomes. In some studies on mice, intermittent dosing was associated with improved survival, and perhaps less toxicity.
MEK1/MEK2 inhibitors have a tendency to cause a papulopustular rash, seen in 57% of patients. Other side effects include diarrhea in 43%, whereas peripheral edema is observed in 26%. More serious adverse effects include hypertension in 12%, rash in 8%, and fatigue in 4%.
Creatine phosphokinase (CPK) levels are high in some patients, though without any evidence of underlying disease processes such as rhabdomyolysis.
Abnormal liver function tests and pneumonitis are also observed, similar to immune checkpoint inhibitors and PD-1 inhibitors. The appearance of cough, difficulty in breathing or abnormal chest signs must be followed up with chest radiography or a CT scan of the chest, and if pneumonitis is present, treatment must be stopped for a time at least.
Ocular toxicity, comprising blurring of vision and reversible chorioretinopathy (especially central serous retinopathy, CSR) is another feature of MEK inhibitor toxicity. Among these, retinal vein occlusion is irreversible. For this reason, a baseline ophthalmologic examination should be recorded. If any visual disturbance occurs, examination should be repeated and compared with baseline findings. If retinopathy is diagnosed, the drug should be withdrawn temporarily. If the retinal appearance and function normalizes within three weeks, and RVO is absent, the drug may be resumed at a lower dosage.
Other adverse effects include nausea, vomiting, constipation, alopecia, and lowered left ventricular ejection fraction. An uncommon adverse effect is the dropped-head syndrome, where the neck extensors become progressively weak because of focal non-inflammatory myopathy. CPK levels are high, and the condition fails to respond to steroids but resolves when the MEK inhibitor is discontinued.
Hallucinations and confusion are rare reactions, presumably due to the penetration of some of these drugs into the central nervous system.
Patients at increased risk of adverse events include those with pre-existing liver derangements.
How Do Antineoplastic Egfr Inhibitors Work?
Antineoplastic epidermal growth factor receptor (EGFR) inhibitors are a class of drugs used to treat hormone receptor-positive breast cancer (breast cancer that depends on hormones such as estrogen to grow), medullary thyroid cancer, advanced head and neck cancer, metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer.
EGFR inhibitors are anti-cancer medications that block the activity of a protein called EGFR. EGFR is found on the surface of some normal cells and is involved in cell growth, also found at high levels on some types of cancer cells, which causes these cells to grow and divide. Blocking EGFR helps in preventing unregulated cell division, thus preventing the growth, and spread of cancer cells.
EGFR inhibitors can be classified into the following:
Tyrosine kinase inhibitors: targets the intracellular domain in EGFR and stops the activity of the EGFR.
Monoclonal antibodies: targets the extracellular ligand-binding domain of EGFR and prevents cell division.
EGFR inhibitors are administered via intravenous (into a vein) and oral routes.
EGFR inhibitors work in the following ways:
They belong to a class of medications called “tyrosine kinase inhibitors” that work by slowing down or stopping the growth of cancer cells.
They work by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.
They block the activity of a protein called "EGFR" and thus prevent unregulated cell division.
HOW ARE ANTINEOPLASTIC EGFR INHIBITORS USED?
Antineoplastic EGFR inhibitors are used to treat conditions such as:
Breast cancer
Non-small cell lung cancer
Medullary thyroid cancer
Metastatic colorectal cancer
Advanced squamous cell carcinoma of head and neck
Pancreatic cancer
Malignant gliomas
What Are Cyclin-Dependent Kinases?
Of the many proteins involved in cell cycle control, cyclin-dependent kinases (CDKs) are among the most important. CDKs are a family of multifunctional enzymes that can modify various protein substrates involved in cell cycle progression. Specifically, CDKs phosphorylate their substrates by transferring phosphate groups from ATP to specific stretches of amino acids in the substrates. Different types of eukaryotic cells contain different types and numbers of CDKs. For example, yeast have only a single CDK, whereas vertebrates have four different ones.
As their name suggests, CDKs require the presence of cyclins to become active. Cyclins are a family of proteins that have no enzymatic activity of their own but activate CDKs by binding to them. CDKs must also be in a particular phosphorylation state — with some sites phosphorylated and others dephosphorylated — in order for activation to occur. Correct phosphorylation depends on the action of other kinases and a second class of enzymes called phosphatases that are responsible for removing phosphate groups from proteins.
How Do CDKs Control the Cell Cycle?
All eukaryotes have multiple cyclins, each of which acts during a specific stage of the cell cycle. (In organisms with multiple CDKs, each CDK is paired with a specific cyclin.) All cyclins are named according to the stage at which they assemble with CDKs. Common classes of cyclins include G1-phase cyclins, G1/S-phase cyclins, S-phase cyclins, and M-phase cyclins. M-phase cyclins form M-CDK complexes and drive the cell's entry into mitosis; G1 cyclins form G1-CDK complexes and guide the cell's progress through the G1 phase; and so on.
All CDKs exist in similar amounts throughout the entire cell cycle. In contrast, cyclin manufacture and breakdown varies by stage — with cell cycle progression dependent on the synthesis of new cyclin molecules. Accordingly, cells synthesize G1- and G1/S-cyclins at different times during the G1 phase, and they produce M-cyclin molecules during the G2 phase (Figure 2). Cyclin degradation is equally important for progression through the cell cycle. Specific enzymes break down cyclins at defined times in the cell cycle. When cyclin levels decrease, the corresponding CDKs become inactive. Cell cycle arrest can occur if cyclins fail to degrade.
Metastatic melanoma is a deadly cancer for which conventional chemotherapy provides little benefit. However, newer therapies involving a pathway called the mitogen-activated protein kinase (MAPK) pathway have demonstrated success in inducing remission.
The MAPK pathway is more accurately termed the RAS-RAF-MEK-ERK pathway, and involves the regulation of cell proliferation and survival. It is constitutionally overactive in 30% of cancers. Two enzymes in this pathway, namely, BRAF and MEK, are target kinases which play crucial roles in the cell cycle.
The first therapies to target this pathway were BRAF inhibitors, but intrinsic and acquired tumor resistance quickly led to treatment failure by reactivation of the MAPK pathway. MEK inhibitors have emerged to partially overcome these resistance mechanisms and are now used in combination with BRAF inhibitors to extend the time to resistance.
MEK is a dual specificity threonine/tyrosine kinase, so called from the term MAPK/ERK kinase. It is a key effector of the three-layered RAS/RAF/MEK/ERK signaling cascade, expressed by seven genes from MAPK1 to MAPK7.
MEK inhibitors bind to and inhibit MEK, inhibiting MEK-dependent cell signaling. This inhibition leads to cell death and the inhibition of tumor growth. These are allosteric binding inhibitors of MEK which inhibit either MEK1 alone, or both MEK1 and MEK2.
What is the mechanism of action of MEK inhibitors?
The MAPK pathway is an intracellular signaling cascade that is involved in the proliferation and survival of tumor cells. Many mutations cause cancer development by activating this pathway, including BRAF and NRAS mutations. MEK is a downstream protein kinase which can be targeted to prevent reactivation of the MAPK pathway in the presence of BRAF or RAS mutations.
Normally, ERK1/2 activation initiates a variety of cellular and nuclear pathways, while also inhibiting Raf activity by a feedback loop to modulate the activity of the MAPK pathway. MEK1/2 inhibition inactivates ERK1/2 and also removes the feedback inhibition on Raf.
Drugs which selectively inhibit the MEK enzymes are able to inhibit growth and to induce the death of cells in the presence of these mutations.
Thus, MEK1/2 is highly selective in inactivating ERK1/2 but leaves other signaling pathways intact. In addition, the non-ATP binding site means they do not typically need to compete with ATP, which is present in very large amounts inside cells. A new ATP-competitive inhibitor has also been designed which is effective in mutants that display drug resistance to the ATP-noncompetitive inhibitors.
The advantages of using combination MEK inhibitor therapy with a BRAF inhibitor is the increased progression-free survival and lower toxicity, when compared with the latter alone.
What are the side effects of MEK inhibitors?
Adverse reactions with MEK inhibitors occur in two stages: immediate (within days of initiation of therapy) and chronic (following several months of exposure). Mild toxicities need not interrupt the treatment, but moderate to severe adverse effects may require temporary withdrawal of the drugs and re-initiation following resolution of the reaction. Such cessation of treatment for short periods does not seem to affect outcomes. In some studies on mice, intermittent dosing was associated with improved survival, and perhaps less toxicity.
MEK1/MEK2 inhibitors have a tendency to cause a papulopustular rash, seen in 57% of patients. Other side effects include diarrhea in 43%, whereas peripheral edema is observed in 26%. More serious adverse effects include hypertension in 12%, rash in 8%, and fatigue in 4%.
Creatine phosphokinase (CPK) levels are high in some patients, though without any evidence of underlying disease processes such as rhabdomyolysis.
Abnormal liver function tests and pneumonitis are also observed, similar to immune checkpoint inhibitors and PD-1 inhibitors. The appearance of cough, difficulty in breathing or abnormal chest signs must be followed up with chest radiography or a CT scan of the chest, and if pneumonitis is present, treatment must be stopped for a time at least.
Ocular toxicity, comprising blurring of vision and reversible chorioretinopathy (especially central serous retinopathy, CSR) is another feature of MEK inhibitor toxicity. Among these, retinal vein occlusion is irreversible. For this reason, a baseline ophthalmologic examination should be recorded. If any visual disturbance occurs, examination should be repeated and compared with baseline findings. If retinopathy is diagnosed, the drug should be withdrawn temporarily. If the retinal appearance and function normalizes within three weeks, and RVO is absent, the drug may be resumed at a lower dosage.
Other adverse effects include nausea, vomiting, constipation, alopecia, and lowered left ventricular ejection fraction. An uncommon adverse effect is the dropped-head syndrome, where the neck extensors become progressively weak because of focal non-inflammatory myopathy. CPK levels are high, and the condition fails to respond to steroids but resolves when the MEK inhibitor is discontinued.
Hallucinations and confusion are rare reactions, presumably due to the penetration of some of these drugs into the central nervous system.
Patients at increased risk of adverse events include those with pre-existing liver derangements.
How Do Antineoplastic Egfr Inhibitors Work?
Antineoplastic epidermal growth factor receptor (EGFR) inhibitors are a class of drugs used to treat hormone receptor-positive breast cancer (breast cancer that depends on hormones such as estrogen to grow), medullary thyroid cancer, advanced head and neck cancer, metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer.
EGFR inhibitors are anti-cancer medications that block the activity of a protein called EGFR. EGFR is found on the surface of some normal cells and is involved in cell growth, also found at high levels on some types of cancer cells, which causes these cells to grow and divide. Blocking EGFR helps in preventing unregulated cell division, thus preventing the growth, and spread of cancer cells.
EGFR inhibitors can be classified into the following:
Tyrosine kinase inhibitors: targets the intracellular domain in EGFR and stops the activity of the EGFR.
Monoclonal antibodies: targets the extracellular ligand-binding domain of EGFR and prevents cell division.
EGFR inhibitors are administered via intravenous (into a vein) and oral routes.
EGFR inhibitors work in the following ways:
They belong to a class of medications called “tyrosine kinase inhibitors” that work by slowing down or stopping the growth of cancer cells.
They work by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.
They block the activity of a protein called "EGFR" and thus prevent unregulated cell division.
HOW ARE ANTINEOPLASTIC EGFR INHIBITORS USED?
Antineoplastic EGFR inhibitors are used to treat conditions such as:
Breast cancer
Non-small cell lung cancer
Medullary thyroid cancer
Metastatic colorectal cancer
Advanced squamous cell carcinoma of head and neck
Pancreatic cancer
Malignant gliomas
What Are Cyclin-Dependent Kinases?
Of the many proteins involved in cell cycle control, cyclin-dependent kinases (CDKs) are among the most important. CDKs are a family of multifunctional enzymes that can modify various protein substrates involved in cell cycle progression. Specifically, CDKs phosphorylate their substrates by transferring phosphate groups from ATP to specific stretches of amino acids in the substrates. Different types of eukaryotic cells contain different types and numbers of CDKs. For example, yeast have only a single CDK, whereas vertebrates have four different ones.
As their name suggests, CDKs require the presence of cyclins to become active. Cyclins are a family of proteins that have no enzymatic activity of their own but activate CDKs by binding to them. CDKs must also be in a particular phosphorylation state — with some sites phosphorylated and others dephosphorylated — in order for activation to occur. Correct phosphorylation depends on the action of other kinases and a second class of enzymes called phosphatases that are responsible for removing phosphate groups from proteins.
How Do CDKs Control the Cell Cycle?
All eukaryotes have multiple cyclins, each of which acts during a specific stage of the cell cycle. (In organisms with multiple CDKs, each CDK is paired with a specific cyclin.) All cyclins are named according to the stage at which they assemble with CDKs. Common classes of cyclins include G1-phase cyclins, G1/S-phase cyclins, S-phase cyclins, and M-phase cyclins. M-phase cyclins form M-CDK complexes and drive the cell's entry into mitosis; G1 cyclins form G1-CDK complexes and guide the cell's progress through the G1 phase; and so on.
All CDKs exist in similar amounts throughout the entire cell cycle. In contrast, cyclin manufacture and breakdown varies by stage — with cell cycle progression dependent on the synthesis of new cyclin molecules. Accordingly, cells synthesize G1- and G1/S-cyclins at different times during the G1 phase, and they produce M-cyclin molecules during the G2 phase (Figure 2). Cyclin degradation is equally important for progression through the cell cycle. Specific enzymes break down cyclins at defined times in the cell cycle. When cyclin levels decrease, the corresponding CDKs become inactive. Cell cycle arrest can occur if cyclins fail to degrade.