How Does Erlotinib Work

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What Is Erlotinib?

What Is Erlotinib?

Erlotinib(CAS:183321-74-6) belongs to a class of drugs known as tyrosine kinase inhibitors. It works by blocking the function of a protein called the epidermal growth factor receptor (EGFR). The EGFR is found on the surface of many cancer cells as well as normal cells. It serves as an “antenna,” receiving signals from other cells and the environment that tell the cell to grow and divide. The EGFR plays an important role in growth and development prenatally and during childhood and helps to maintain normal replacement of old and damaged cells in adults. However, many cancer cells have unusually large amounts of the EGFR on their surface, or their EGFR has been altered by mutation of the DNA that carries the genetic code for the protein. The result is that the signals coming from the EGFR are much too strong, leading to excessive cell growth and division, a hallmark of cancer.

How Does Erlotinib Work?

The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine 1

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kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.

What Diseases Does Erlotinib Mainly Treat?

(1) Lung cancer

Erlotinib in unresectable non-small cell lung cancer when added to chemotherapy improves overall survival by 19%, and improved progression-free survival (PFS) by 29%, when compared to chemotherapy alone.The U.S. Food and Drug Administration (FDA) approved erlotinib for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen.

In lung cancer, erlotinib has been shown to be effective in patients with or without EGFR mutations, but appears to be more effective in patients with EGFR mutations.Overall survival, progression-free survival and one-year survival are similar to standard second-line therapy (docetaxel or pemetrexed). Overall response rate is about 50% better than standard second-line chemotherapy.Patients who are non-smokers, and light former smokers, with adenocarcinoma or subtypes like BAC are more likely to have EGFR mutations, but mutations can occur in all types of patients. A test for the EGFR mutation has been developed by Genzyme.

(2) Pancreatic cancer

In November 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.

(3) Resistance to treatment

Erlotinib bound to ErbB1 at 2.6A resolution; surface colour indicates hydrophobicity.As with other ATP competitive small molecule tyrosine kinase inhibitors, such as imatinib in CML, patients rapidly develop 2

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resistance. In the case of erlotinib this typically occurs 8–12 months from the start of treatment. Over 50% of resistance is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue (T790M).Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives ERBB3 dependent activation of PI3K.

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