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Old 01-19-2014, 01:41 AM   #1
donocco
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Mekinist (Trametinib) a MEK Kinase inhibitor

We have had discussions on various inhibitors like C-MET (the inhibiting drug is ARK-195) and P13K inhibitors like
BMK-120 which I believe is caled Buparlisib) I found another signal tranduction inhibitor. This inhibits the MEK kinase. There is a pathway where RAS -RAF-MEK-ERK
each abbreviation is a protein kinase, and the one before it stimulates the activity of the one after it. This is downstream signal transduction. After ERK is stimulated the cancer cells are stimulated to proliferate. So the idea of Trametinib is to prevent ERK stimulation by blocking MEK stimulation. In theory this makes sense.

Mekinist (Trametinib) is not experimental but is an FDA approved drug used to treat metastatic melanoma that has a type of BRAF-600K mutation whatever that is. Ill look it up. I studied the drug to see the effect of a MEK inhibitor as Im sure they could eventually find use in breast and other cancers.

The dose of Mekinist is 2mg daily and the patients with metastatic Melanoma who took Mekinist basically lived about four and a half months vs the ones on just IV chemo (either Dacarbazine or Paclitaxel). These patients lived only about 1.5 months.

The list of side effects of Mekinist is long and severe. It can cause severe rashes and if they continue the drug has to be discontinued. It can cause pneumonitis and if the patient develops breathing difficulties the drug has to be discontinued. It can cause retinal detachment, Retinal Vein Occlusion and ultimate blindness. Should visual problems develop the drug has to be discontinued. It can also cause severe heart problems and if the left ventricular ejection fraction is seen to progressively decrease, the drug has to be discontinued.
Other side effects listed for Mekinist are
1. Lymphedema
2. anemia
3 Diarrhea (can be severe and is common)
4. Edema
5 High blood pressure
6. Stomatitis.
7. Bleeding and others.

Ill research some other MEK inhibitors that are in the pipeline and experimental. I certainly hope that this long list of serious side effects is not a general phenomenon with MEK inhibitors. The idea of inhibiting the MEK kinases as a cancer treatment is theoretically sound. Hopefully other MEK inhibitors will be less toxic

Paul
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Old 01-19-2014, 01:57 AM   #2
donocco
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Re: Mekinist (Trametinib) a MEK Kinase inhibitor

I dont want to leave things incomplete so I studied BRAF
mutation. Actually it involves that RAF-RAS- MEK-ERK signalling. BRAF is actually B-RAF so it is a RAF protein that has been mutated with a single amino acid substitution. This single amino acid substitution creates a more active RAF so the RAS-RAF-MEK-ERK pathway becomes hyperactive with increased cancer cell growth.

Paul
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Old 01-19-2014, 10:47 AM   #3
'lizbeth
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Re: Mekinist (Trametinib) a MEK Kinase inhibitor

Paul,

Thanks again. I was in a KRAS study. Do you have any information on that mutation?
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Old 01-19-2014, 02:43 PM   #4
donocco
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Re: Mekinist (Trametinib) a MEK Kinase inhibitor

Elizabeth

I looked at KRAS and got some info. KRAS is a cytoplasmic protein that activates both RAS and P13K. Therefore you get increased cancer cell growth from two signal transdution pathways. P13K stimulation to AKTto MTORC1 to cell growth. Also RAS-RAF-MEK-ERK to increased cell proliferation. Apparaently the mutation involves a single amino acid substituion in the normal protein. A glycine is changed to a Valine. Both Glycine And Valine are amino acids. Proteins are thousands of amino acids linked together in a chain like a string of colored beads. Lets say you have a chain of red-blue- purple-black-brown-green-green beads strung together in a chain repeated again and again so that their are thousands of amino acids in the protein. If a single amino acid changes in a sensitive place the protein Functions abnormlly. So in the colored beads=amino acid analogy if in the active site of the protein (enzyme, all enzymes are proteins) there is one color change (amino acid change)
the function of the enzyme is altered. The amino acid sequence that is repeated over and over again (red-blue-purple-black-brown-green-green ends in green-purple instead of green-green in one vital area. This single change makes the whole protein function change.
As DNA goes to RNA and RNA goes ultimately to an amino acid (3 DNA bases= one amino acid and this is called a codon) these abnormal amino acid substitutions (glycine changing to Valine in the KRAS mutation) are due ultimately to DNA mutations which occur all the time
(radiation, chemicals, chromosome breakages etc). This is why cancer is so complicated. I hope this makes some sense.

The KRAS mutation seems to be implicated mostly in Pancreatic cancer and colon cancer. In the brief research I did I didnt see breast cancer mentioned. Is there a KRAS mutation involved in breast cancer?

Paul

PS Here is the chemical structure of an amino acid

CH3CHNH2COOH this is the simplest one, glycine. When the amino acids link together to form proteins, the COOH part (the acid part) of one Amino Acid links to the NH2 part (Amino part) of another amino acid forming a bond.
Im sorry there is so much chemistry.
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Old 01-20-2014, 10:49 AM   #5
'lizbeth
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Re: Mekinist (Trametinib) a MEK Kinase inhibitor

Paul,

There is a researcher that contacted breast cancer survivors through the Army of Women to test for the KRAS mutation.

I do not believe KRAS is one of the more common mutations of cancer from reading an article that Lani had posted a while back.

Oh COOH, carboxyls. I came across these when I was trying to grasp PCT - which is a deactivation of the uroporphyrinogen decarboxlyase enzyme in the 5th step of Heme production.

I was at the library trying to find material to read to learn more about the basics of these pathways and protein kinases. Nothing I could find locally was helpful.
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Old 01-21-2014, 04:00 AM   #6
donocco
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Re: Mekinist (Trametinib) a MEK Kinase inhibitor

Elizabeth

That is over my head mostly. I assume you were studying
Porphyria. Heme is the protein in Hemoglobin. I never enjoyed biochemistry but did ok grade wise because it is all memory. Now Im finding I have to relearn it to understand cancer signal transduction and cancer cell glucose metabolism

Paul
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Old 01-21-2014, 12:29 PM   #7
'lizbeth
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Re: Mekinist (Trametinib) a MEK Kinase inhibitor

Paul,

I had a chance to observe a diagnosis of Porphyria Cutanea Tarda - likely a complication from Hemachromatosis.

The symptoms were anemia, blisters, skin darkening and tearing. Byproducts of the heme process - the porphyrins build up in the skin and the liver.

Fascinating stuff, especially when most think of anemia as an iron deficiency. Too much iron deactivates the uroporphyrinogen decarboxalyse enzyme by approximately 25%.

It is another of the body's response mechanism to correct for one imbalance by adjusting another process. And a situation which shows how fascinatingly complex beings that we all are.

and this is why we are still grasping for a "cure" for cancer. It may not be simple, but when all the pieces are put together we will ask, why didn't we grasp this before - it seems so obvious.
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