Tarceva mechanism of action

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of the MOA.

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
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]




When the balance between cell division and apoptosis is disrupted, overproliferation can occur, leading to cancer.[2]

Cancer cell proliferation is mediated in part by the interactions between membrane receptors and growth factors found throughout the body.[1]
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
HER1/EGFR is made up of 3 parts:[1]
  • an intracellular tyrosine kinase domain
  • a short transmembrane domain
  • an extracellular ligand-binding domain
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]
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]
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]
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

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  • EGFR receptor overexpression, which can result in increased signaling activity
  • EGFR mutations, which may lead to tumorigenicity
Tarceva: 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]

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]
References: 1. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7:2-8. 2. Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol. 2003;7:3-14. 3. Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist. 2002;7:31-39. 4. 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. 5. Akita RW, Sliwkowski MX. Preclinical studies with erlotinib (Tarceva). Semin Oncol. 2003;30:15-24.
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