Watch Tarceva in action—download an animation. Or, download a printable pdf of the MOA.
While the mechanism of clinical antitumor action of Tarceva has not been fully characterized, nonclinical models show that Tarceva blocks EGFR-mediated downstream signaling activity, including those signals potentially initiated by mutated receptors. By preventing overproliferation and permitting apoptosis of cancer cells, Tarceva may help restore normal cellular function. [5]
Mechanism of inhibition: HER1/EGFR tyrosine kinase inhibitor
As a small-molecule HER1/EGFR Tyrosine Kinase Inhibitor (TKI), Tarceva inhibits cellular signaling by competing with ATP for the active site of the intracellular tyrosine kinase domain. [4]
- EGFR mutations, which may lead to tumorigenicity
- EGFR receptor overexpression, which can result in increased signaling activity
HER1/EGFR dysregulation
Dysregulation of HER1/EGFR disrupts normal cellular growth and may lead to neoplasia and the inhibition of apoptosis.
This may occur through a number of different mechanisms: [3]
- EGFR ligand overexpression, which can result in increased EGFR signaling activity
Two of the signal transduction pathways from HER1/EGFR are directly involved with cell division and apoptosis. In fact, HER1/EGFR is largely responsible for normal cellular growth. These normal cellular processes can become tumorigenic when the HER1/EGFR functions inappropriately. [2]
After ATP-phosphorylation, the receptor recruits adaptor proteins and signal transduction enzymes from the cytoplasm, which leads to further activation of multiple downstream pathways. [1]
When a ligand binds to the extracellular domain, the HER1/EGFR activates and dimerizes with another HER family receptor. This leads to transphosphorylation, or ATP-phosphorylation, of the adjacent intracellular tyrosine kinase domains. [1]
HER1/EGFR is made up of 3 parts: [1]
- an intracellular tyrosine kinase domain
- a short transmembrane domain
- an extracellular ligand-binding domain
HER family of receptors: The role of EGFR
EGFR is a member of the HER family of membrane receptors. It plays a central role in the regulation of cell division and death. [1]
There are 4 receptor types in the HER family: [1]
- HER1/EGFR
- HER2
- HER3
- HER4
Cancer cell proliferation is mediated in part by the interactions between membrane receptors and growth factors found throughout the body. [1]
When the balance between cell division and apoptosis is disrupted, overproliferation can occur, leading to cancer. [2]
Cancer cell proliferation: Aberrant cell signaling
Dysregulation of receptor-mediated signaling pathways disrupts
Normal cellular patterns by increasing cell proliferation and inhibiting programmed cell death, or apoptosis.[1]
Tarceva in action
To understand how Tarceva works, it is helpful to review:
- Cancer cell proliferation
- The Human Epidermal Receptor (HER) family of receptors and the role of HER1/Epidermal Growth Factor Receptor (EGFR)
- Dysregulation of HER1/EGFR
- Tarceva mechanism of inhibition
- Tarceva clinical results
References
- Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7:2-8.
- Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol. 2003;7:3-14.
- Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist. 2002;7:31-39.
- Arteaga CL, Ramsey TT, Shawver LK, Guyer CA. Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site. J Biol Chem. 1997;272:23247-23254.
- Akita RW, Sliwkowski MX. Preclinical studies with erlotinib (Tarceva). Semin Oncol. 2003;30:15-24.
