Axitinib, known by the brand name Inlyta, is a medication used in modern cancer treatment. It is primarily prescribed for advanced renal cell carcinoma (RCC), a form of kidney cancer, often after other treatments have failed. This drug is a targeted therapy, designed to interfere with specific molecules involved in the growth and spread of cancer cells. This approach allows for a more focused attack on the cancer.
The Role of Angiogenesis in Cancer
To understand how Axitinib works, it is helpful to understand angiogenesis, the formation of new blood vessels from pre-existing ones. This process is a normal part of growth and healing, such as in wound repair. Solid tumors also depend on this process to survive and grow.
Tumors require their own blood supply to deliver the oxygen and nutrients necessary for expansion. To achieve this, cancer cells release chemical signals that stimulate new blood vessel growth into the tumor. A primary chemical messenger is a protein called Vascular Endothelial Growth Factor (VEGF). The release of VEGF triggers an “angiogenic switch,” tipping the body’s balance in favor of creating new blood vessels to feed the tumor, which also provides a pathway for metastasis.
The blood vessels formed by tumor-driven angiogenesis are often abnormal, leaky, and irregularly shaped. This reliance on VEGF-driven blood vessel formation makes the VEGF pathway a target for cancer therapies. Disrupting this process is intended to cut off the tumor’s supply lines.
Identifying the Molecular Target
For VEGF to initiate blood vessel formation, it must communicate its message to endothelial cells, which line the blood vessels. It does this by binding to specific docking sites on the surface of these cells called VEGF receptors (VEGFRs). The interaction between VEGF and its receptors is highly specific.
VEGF receptors belong to a family of proteins known as receptor tyrosine kinases. When the VEGF protein binds to the external portion of these receptors, it causes two of them to pair up in a process called dimerization. This pairing activates the internal part of the receptor, the tyrosine kinase domain. The activation triggers phosphorylation, which sets off a cascade of signals inside the endothelial cell that instructs it to form new blood vessels. The VEGFR’s tyrosine kinase function is the precise molecular target for drugs designed to halt angiogenesis.
The Inhibition Process of Axitinib
Axitinib is a potent and selective tyrosine kinase inhibitor (TKI). Its primary function is to block the activity of VEGF receptors, specifically VEGFR-1, VEGFR-2, and VEGFR-3. Unlike therapies that work outside the cell, Axitinib is a small molecule that can pass through the cell membrane and act directly on the receptor inside the endothelial cell.
The drug works by competing with adenosine triphosphate (ATP) for the ATP-binding pocket on the VEGF receptor. The receptor’s tyrosine kinase function depends on using energy from ATP to send signals. By lodging itself in this binding pocket, Axitinib physically prevents ATP from binding. This action jams the receptor’s machinery, so even if VEGF binds to the receptor, phosphorylation cannot occur and the signaling cascade is shut down. Axitinib has a very high affinity for the ATP-binding sites on VEGFRs, making its action highly selective.
Consequences of VEGF Pathway Blockade
When Axitinib successfully inhibits the tyrosine kinase activity of VEGF receptors, the immediate result is the interruption of the pro-angiogenic signals that the tumor relies upon. The endothelial cells lining the blood vessels no longer receive the instructions to multiply and build new vessel structures. This direct blockade of the VEGF signaling pathway leads to an anti-angiogenic effect within the tumor’s microenvironment.
The denial of a new and expanding blood supply has significant consequences for the tumor. Without the constant delivery of oxygen and nutrients, the tumor is effectively starved. This can halt the tumor’s growth, prevent it from increasing in size, or even cause the tumor to shrink.
How the Mechanism Explains Common Side Effects
The mechanism that makes Axitinib effective also explains its common side effects. The VEGF signaling pathway is not exclusive to tumors; it also helps maintain the function of normal blood vessels. When the drug inhibits VEGFRs to stop tumor angiogenesis, it affects these normal physiological processes.
A common side effect of Axitinib is hypertension, or high blood pressure. The VEGF pathway is involved in producing nitric oxide in endothelial cells, which helps blood vessels relax. By inhibiting this pathway, Axitinib can decrease nitric oxide, causing blood vessels to constrict and blood pressure to rise.
Another frequent side effect is diarrhea. The inhibition of VEGF receptors can disrupt the normal function and integrity of the blood vessels supplying the gut. This disruption can lead to the gastrointestinal issues experienced by patients. These side effects are a direct outcome of the drug’s specific mechanism of action impacting normal body systems.