Mechanism of action and Side effects of Everolimus

Everolimus is an immunosuppressant-targeted anticancer drug that can be used for a number of different types of cancers, including metastatic renal cell carcinoma (mRCC), breast cancer (advanced or high-risk early stage), squamous cell carcinoma, subventricular giant cell astrocytoma (SEGA), renal angiomyolipoma, and neuroendocrine tumours.

Mechanism of action

Everolimus is an mTOR inhibitor. In some types of cancer, mTOR is activated, which causes cancer cells to grow and create new blood vessels. Everolimus has a high affinity for FK506 binding protein-12 (FKBP-12), which forms a drug complex that inhibits mTOR activation. This inhibition reduces the activity of downstream effectors, leading to blockage of cell progression from G1 to S phase and subsequent induction of cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factors, resulting in decreased expression of vascular endothelial growth factor. Inhibition of mTOR by everolimus results in reduced cell proliferation, angiogenesis and glucose uptake.

In addition, everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signalling in T cell responses to alloantigens and therefore acts at a later stage than the calmodulin phosphatase inhibitors cyclosporine and tacrolimus. Everolimus also improves effector T cell status, increases cytotoxicity activity (perforin, granzyme), enhances proliferation (Ki67), and up-regulates activation markers (CD38, CD69), thereby further enhancing effector cell function.

Side effects

Common side effects of Everolimus include:

• Cough, shortness of breath

• Infection, including in the blood, especially when white blood cell count is low

• Anemia which may require blood transfusion

• Bruising, bleeding

• Swelling of the face, throat, arms and legs

• Diarrhea, nausea, vomiting

• Sores in mouth which may cause difficulty swallowing

• Weight loss, loss of appetite

• Painful and frequent urination

• Weakness, tiredness

• Cold symptoms such as stuffy nose, sneezing, sore throat

• Fever Rash
  

Occasionally. Some can be serious:

• Fluid around the lungs or damage to the lungs which may cause shortness of breath

• New or worsening diabetes

• High blood pressure which may cause blurred vision

• Blood clot, which may cause belly pain

• Constipation

• Dry mouth

• Dizziness, headache

• Feeling of “pins and needles” in arms, legs

• Difficulty sleeping, worry, panic, depression

• Pain in arms legs, chest, back

• Chills

• Radiation Recall syndrome which may cause swelling and redness of the area of radiation

• Hand-foot syndrome (palmar-plantar erythrodysesthesia) redness, pain or peeling of palms and soles

• Itching, dry skin, acne, change in nails

• Swelling and redness of the whites of the eye, eyelids

• Changes in taste
  

Rare and serious, In 100 people receiving Everolimus, 3 or fewer may have:  

• Heart attack

• Abnormal heartbeat

• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat 

• Non-healing surgical site

• Kidney damage which may cause swelling, may require dialysis A new cancer (including leukemia) resulting from treatment of a prior cancer