TARCEVA LUNG CANCER AND EPIDERMAL GROWTH FACTOR INHIBITORS

 (keywords, Tarceva, lung cancer, epidermal growth factor receptor, Iressa, HKI 272, non-smoker's lung cancer, EGFR, EGF, T790m mutation, Tarceva treatment, second mutation, Tarceva and lung cancer,  treatment for lung cancer, EGFR, epidermal growth factor, egfr antibody, egfr inhibitor, excerpted and updated from our book Lung Cancer and Mesothelioma).  

15.0  THE EPIDERMAL GROWTH FACTOR PATHWAY   

  15.01   Cell Signaling  and a Basic Model of Cancer

The human body has a complex system of signaling between cells with gene duplication a normal part of this process.  Duplication is necessary for growth, repair of damaged cells and other functions.    Proteins signal other cells to initiate replication but mutation and malfunction in these growth factors are a part of cancer, as these growth factors prompt excessive and uncontrolled duplication. 

    15.02 Epidermal Growth Factor Receptor

In recent year, the epidermal growth factor receptor (EGFR) has become the target of new drugs.  The EGFR signaling pathway regulates growth, survival, proliferation, and differentiation in our cells.

“The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway. .. The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling."  Tartora, (2), See also FDA (1) .  See also (Baselga 24).   

 15.03 Structure of EGFR   

The receptor  has two basic parts.   The first part of the receptor is called the extracellular ligand-binding domain.  There it receives a signal from the growth factor and a process called ligand binding occurs.  Once binding occurs, a signal is sent to the second part of the receptor called the tyrosine kinase domain.  There a process called autophosphorylation occurs.   A chemical change occurs and signals are sent to other cells.   In cancer, these signals are abnormal, and thus other cells are told to duplicate are perform other aberrant functions.  "The tyrosine kinase activity of phosphorylated EGFR in cancer cells results in the phosphorylation of downstream proteins that incite cell proliferation, invasion, metastasis, and inhibition of apoptosis.  Dowell (71).

Cancer drugs can work in two basic ways, they can try to prevent binding at the ligand-binding domain,  or prevent autophosphorylation in the tyrosine kinase.  The fact that there are two separate functions means that drugs may later be combined.  Cells both give and receive signals.  A particular growth factor is involved both by receiving abnormal signals from other cells and giving them. 

    15.05 Expression of Epidermal Growth Factor and Lung Cancer

"The high level of expression of the EGFR on non small cell lung cancer (NSCLC) and the important role of EGFR in signal transudation make it potentially an excellent target for antibody directed therapy." Zhonghua (20).   One report found overexpression of EGF in 50% of lung adenocarcinomas, while another study found EGFR expression in 94 of 169 (56%) non small cell cases. Pass (3), Cox (4)  

15.1 WHO BENEFITS FROM TARCEVA

   15.11 Overview

Iressa and Tarceva are similar drugs with both inhibiting the activity of EGFR.  More specifically, each inhibits the action of the tyrosine kinase portion of the EGFR.  Tarceva is reputed to be stronger, and Iressa is no longer commercially available in the United States. Iressa and Tarceva have shown success in stabilizing disease, improving symptoms, and achieving reduction of disease in patients whose tumros are EGFR positive showing expression of a mutated EGFR.  Since Tarceva only targets a specific growth factor receptor, it impacts only a limited number of cells causing fewer side effects and disruption in the body.

   15.12 Use with Non-Smokers and Light Former Smokers

Initial studies with Iressa showed a small number of patients had responses to the drug.   See  FDA (47).   AT Harvard, Lynch was able to identify who responded, finding that 8 of 9 patients had specific identifiable damage to the tyrosine kinase portion of the EGFR.   Lynch (55).  All the patients who responded had never smoked or were light former smokers.  The damage to the tyrosine portion of the EGFR meant that this was driving their cancer and that stopping this signalling could provide dramatic help to the patient.  Lynch's findings have been duplicated in a number of subsequent studies. 

"Two groups of investigators simultaneously reported the important discovery that most patients who had a response to gefitinib had tumors with somatic mutations of EGFR — small deletions, insertions, or point missense mutations — that affect critical amino acids in the ATP-binding cleft of the tyrosine kinase domain of the receptor.   This very cleft is the binding site for the inhibitor drugs."  Dowell (71).  "EGFR mutations in exons 19 or 21 are correlated with clinical factors predictive of response to gefitinib and erlotinib. Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation. These observations warrant confirmation in a prospective study and exploration of the biological mechanisms of the differences between the two major EGFR mutations. ^{" "}Presence of EGFR mutations was the only independent predictor for disease control."   Chou (58).

       15.13 Adenocarcinoma and Subtypes

The patients who responded in Lynch's studies all had adenocarcinoma or BAC subtype.  Lynch (55) See also (52) and Garbiter (53).
Other studies have also found adenocarcinoma and BAC formed of patients with the EGFR mutation who responded.  However, a small percentage in some studies were outside this group.   Sasaki found 12.5% of patients who responders were outside the adenocarcinoma target group.  Sasaki (69).

       15.14 Other Patterns of Response

Less easy to explain, women and Japanese have higher rates of response.  FDA (62).   Additionally, while we can predict who is likely to have the mutation, there remains some uncertainty.  One study found  "EGFR mutations were present in 35 patients (36.8%). These mutation statuses were significantly correlated with gender (women 73.3% vs. men 20%, p < 0.0001), smoking status (never smoker 69.4% vs. smoker 16.9%, p < 0.0001), pathologic subtypes (adenocarcinoma 45.1% vs. nonadenocarcinoma 12.5%, p = 0.0089) and differentiation status of the lung cancers (well 51% vs. moderately or poorly 18.4%, p = 0.0021). "  Sasaki (69).  The abstract does not indicate the extent of smoking or the characteristics of non-adenocarcinoma patients.

         15.15 EGFR Testing

Since we can identify those likely to respond based upon the area of genetic damage, it makes sense to test patients to identify this.  A press release for testing performed at the Harvard Medical School explains:

"The Harvard Medical School - Partners HealthCare Center for Genetics and Genomics (HPCGG) has begun to offer a test that gives doctors a valuable new tool to guide the treatment of certain lung cancers.  The test – known as EGFR Kinase Domain Sequencing – was developed in cooperation with the pathology laboratories of Brigham and Women’s Hospital and Massachusetts General Hospital, and detects mutations in a critical part of the gene called epidermal growth factor receptor (EGFR). The gene mutation is present in a subset of non-small cell lung cancers, most commonly adenocarcinomas and bronchoalveolar carcinomas arising in nonsmokers. When the mutation is present, it is associated with a response to the anti-cancer drug Iressa (gefitinib). Iressa works by blocking the function of the mutant EGFR protein that these cancer cells need to survive and proliferate."  Similar testing is being performed in Japan.

Non-smokers or those with limited smoking histories will want to consider Tarceva, and have EGFR testing performed to determine if they have the mutation that predicts response.   

15.16 Tarceva for Smokers  

The studies have found those who responded (tumor reduction of 50% or more) were non-smokers.  It did find a smaller number of light  former smokers. Sasaki's (69)found that while most of the patients with the EGFR mutation are non-smokers, a few smokers had it.  (The extent of smoking history was not stated in the abstract).   Prior research suggests those are likely to be former smokers with limited smoking histories.  Hsieh likewise found a small percentage of smokers with the mutation who responded to Tarceva.  Hsieh (70).  Those with greater smoking histories are unlikely to have responses to Tarceva.

Thus smokers who quit or who have limited histories might want to obtain the EGFR test. If the test is positive, the drug is likely to be beneficial. Whether Tarceva can help stabilize the disease of those who do not have the mutation is controversial.  Many believe response is associated with an EGFR driven cancer suppressed by Tarceva.  Some believe that EGFR is not so easily measured and that drugs like Tarceva may help stabilize disease (few responses are seen in those without the mutation). 

15.2 Omitted

15.3 TARCEVA AND CHEMOTHERAPY AND RADIATION

15.31 Human Clinical Trials Using Iressa and Chemotherapy

Two large scale clinical trials found Iressa did not improve the effects of chemotherapy.  (50).  The well-publicized clinical trial compared patients who took chemotherapy and Iressa with those who took chemotherapy alone.   Surprisingly the group taking the combination with Iressa did no better than the group using chemotherapy alone.  Rates of survival, partial response, and complete response were similar between the two experimental groups using.     

15.4 SIDE EFFECTS OF TARCEVA  

    15.41 Rash

The most prevalent side effect is a localized rash.  Patients have reported it but it appears to be localized and not unusually serious.  , Some studies have found the existence of a rash indicates Iressa is working with patients with rashes having  longer survival rates.  A limited number of other studies have questioned the correlation.  (53)    "Patients who developed any degree of skin rash had prolonged time to disease progression with median of 6 months (95% CI: 2.56, 15.5) versus patients without skin rash median 3 months."  Dudek (66).

        15.411 Treatment of the Rash. 

Some suggest a moisturizing product is helpful in addressing the rash.  At a non-small cell lung cancer newsgroup, patients and care-givers discuss dealing with drug side effects and offer suggestions.
See www.acor.org

    15.42 Diarrhea

Diarrhea though not particularly severe has also been reported.   

    15.43 Pneumonitis

One serious side effect associated with Iressa wasn an unusual form of pneumonia. Pneumonia is associated with lung cancer and chemotherapy generally. However, there have been a series of pneumonitis deaths linked to Iressa initially reported in Japan:
“We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities in chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.” Inoue (22)

FDA describes the onset this way, “patients often present with the acute onset of dypnea (difficulty breathing), sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization.” FDA (1).
Careful monitoring for this side effect has been recommended. Patients on Iressa should monitor temperature rises, fevers, and immediately report problems to their oncologist. FDA suggests that “persons with concurrent pulmonary fibrosis have a higher mortality rate. This would presumably includes people with silicosis, asbestosis and similar fibrotic disease.

15.5 RESISTANCE AND DEVELOPMENT OF A SECOND MUTATION AFTER TREATMENT

       15.51 The Problem of  Drug Resistance 

Patients with EGFR damage usually initially respond but frequently the tumor recurs.  Scientists have found that a second EGFR pathway develops following initially successful therapy with Tarceva or Iressa. 

"The study involved six patients who had received treatment with gefitinib or erlotinib and who later developed acquired resistance. Researchers studied samples taken from the patients' tumors at different times before and during treatment. All of the tumors had the kinds of mutations in the EGFR gene that were previously associated with responsiveness to these drugs. But, in three of the six patients, they found that tumors that grew despite continued therapy had an additional mutation in the EGFR gene, strongly implying that the second mutation was the cause of drug resistance. Further biochemical studies showed that this second EGFR mutation, which was the same in all three tumors, could confer resistance to the EGFR mutants normally sensitive to these drugs. The mutation is analogous to a mutation that makes other kinds of tumors resistant to another targeted therapy, imatinib mesylate (Gleevec®),"  Acquired resistance to Gleevec is a well-known problem, and understanding its molecular causes has led to the design of other drugs that overcome that resistance,"  Why Some Cancers Stop Responding (62) .

These findings have been duplicated in several recent studies.  Pao (68). Yokoyama (65).

       15.52 Location of  Second Mutation at  T790M

A primary cause of resistance appears to be developement of a second mutation at the T790M location.   Pao (68) writes, "We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. "  The mutation appears to develop in response to Tarceva and is rarely found before.  "All four constructs carrying the T790M amino acid substitution demonstrated high-level resistance, with persistent generation of phosphorylated EGFR (despite Tarceva)."  Kobayashi (72)

   15.53 Addressing The Second Mutation 

The development of the second mutation allows EGFR signalling and cell duplication.    The doctor should theoretically have an easier task with a patient who initially responded to Tarceva but has now developed the second mutation.   First, testing to confirm the mutation makes sense.  Additionally pan-inhibitors can be considered for this subgroup.     

"Pan inhibitors permanently and irreversibly stop certain functioning of EGFR.   Initial cell studies have indicated these stronger inhibitors can work against the resistant cells with the mutation.  To determine whether the T790M mutation leads to resistance to EGFR inhibitors that have different molecular structures and mechanisms, we screened four commercially available EGFR inhibitors (AG1478, cetuximab, erlotinib, and CL-387,785) using cells that were transiently transfected with the delL747–S752 construct and the delL747–S752+ T790M construct. We consistently found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, strongly inhibited EGF-induced phosphorylation  While this may not be a valid alternative for many patients, it may make sense for patients whose cancers have been shown to be associated with EGFR."  Kubayashi (71)  

"Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation."

15.54 MET Mutation

15.6 PAN-INHIBITORS

Sharma explains:

"one of the main challenges in the treatment of NSCLC is to design inhibitors that can overcome the steric interference to drug binding conferred by the T790M mutation. Irreversible inhibitors seem to show some promise in this regard. In most cases, irreversible inhibitors form a covalent bond with crucial cysteine residues — Cys797 within EGFR or Cys805 within ERBB2 — in the active site of the respective enzymes. Given the fact that only EGFR and ERBB2 (as opposed to ERBB4) have cysteines at these corresponding positions, irreversible ErbB inhibitors show very high specificity for EGFR and ERBB2. Previous studies from our laboratory have shown that the irreversible dual EGFR and ERBB2 inhibitors, HKI-272 (Ref. 136) and HKI-357 (Ref. 37), as well as the irreversible EGFR inhibitor EKB-569 (Ref. 137) were all able to overcome gefitinib resistance owing to T790M in cis with an L858R mutation in EGFR. Sharma (5)

15.61. HKI 272

One study found pan-inhibitor HKI 272 effective with tumor cells in a laboratory setting. "HKI 272 is effective in inhibiting various lung cancer mutations- "HKI-272 is effective in growth inhibition of Ba/F3 cells transformed with EGFRvIII, EGFR-L858R, and EGFR-L858R-T790M."   Ji (1)

15.62 Lapanatib

"Pan  inhibitors permanently and irreversibly stop certain functioning of EGFR.   Initial cell studies have indicated these stronger inhibitors can work against the resistant cells with the mutation.  To determine whether the T790M mutation leads to resistance to EGFR inhibitors that have different molecular structures and mechanisms, we screened four commercially available EGFR inhibitors (AG1478, cetuximab, erlotinib, and CL-387,785) using cells that were transiently transfected with the delL747–S752 construct and the delL747–S752+ T790M construct. We consistently found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, strongly inhibited EGF-induced phosphorylation  While this may not be a valid alternative for many patients, it may make sense for patients whose cancers have been shown to be associated with EGFR." 

"Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells.... Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation."Kubayashi

15.63. BMS 690514

"BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation."

15.64 Testing and Approach

15.7 OTHER EPIDERMAL GROWTH FACTOR AND COMBINED THERAPIES

15.71 Erbitux

"Erbitux  is a new drug from Imclone, previously called Cetxumad or IMC-C225.   It "is believed to interfere with the growth of cancer cells by binding to EGFR so that the normal (natural) epidermal growth factors cannot bind and stimulate the cells to grow."  FDQ.gov.  It was originally approved for treatment of colon cancer, but many believe it will also assist in the treatment of lung tumors.  Erbitux attempts to prevent the initial binding while Iressa and Tarceva try to prevent phosphylation after binding.  Basically Erbitux binds to the EGFR before EFR can.

15.72 Herceptin

Herceptin (Trastuzumab) attacks Erb2, a related member of the Erb family of receptors which includes EGFR.  Herceptin has been FDA approved for metastatic breast cancer. The drug targets Erb2 which is a “molecular marker of ductal breast cancer although it is overexpressed in other adenocarcinomas as well (e.g. endometrial, colorectal and lung cancers).” While drug effectiveness is organ specific, lung, colon, and breast are categorized as solid tumors and have some common characteristics. For example, the chemotherapy drug Taxol is used for both breast and lung cancer. 

15.8 EGFR vIII and SQUAMOUS CELL CANCER

While adenocarcinoma is the principal type of EGFR positive cancer, others occasionally arise, and a particular mutation sometimes associated with squamous cell cancer has been studied. 

15.81 What is EGFR vIII.

EGFR is a particular mutation of the EGFR.  "The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvlll, de2–7 EGFR or ΔGFR) has an in-frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvlll has been reported to be tumorspecific and has oncogenic potential, it is being investigated as a potential therapeutic target."  Okamato (77)    "Overexpression of EGFRvIII  is oncogenic in the lung tissues. Further, the abrogation of EGFR VIII expression by withholding doxycycline causes regression of the lung tumors, demonstrating that these tumors are dependent on the activated EGFR pathway."  Li (74) , Wikstrand (76).  

EGFRvIII presents a different clinical target than EGFR: 

"Treatment with gefitinib or erlotinib of patients with lung cancer having EGFR kinase domain mutations often generates dramatic clinical responses.  However, the effectiveness of gefitinib or erlotinib in lung adenocarcinoma with WT EGFR or in other histological subtypes, such as squamous cell carcinoma, is limited^.  Furthermore, it has been shown in preclinical and clinical trials that gefitinib or erlotinib are largely ineffective in inhibiting the function of the EGFRvIII mutant."   While the focus of Tarceva treatment has been adenocarcinoma, squamous cell carcinoma is becoming a target with EGFR vIII.  EGFR mutation for non-smokers is the primary target for Tarceva while smoking history would appear less significant with EGFR vIII mutations, though more investigation is needed. 

15.82 Ji found that EGFRvIII mutation is present in 5% of squamous cell cancers.  Ji (74), Okamato (77).

15.83 Treatment with HKI 272

Ji found the cells responded well to the pan-inhibitor HKI 272.    "HKI-272 dramatically inhibits the growth of EGFRvIII-transformed cells in vitro and tumor growth in vivo."  Ji (74)

15.84 Monoclonal Antibodies

 Similar results were seen with another experimental drug.  AB 806 is an experimental monoclonal antibody and its author its mode of action:

"To date, 2 major types of anti-EGFR agents have entered the clinical setting: anti-EGFR antibodies and small-molecule EGFR tyrosine kinase inhibitors (TKIs)        Anti-EGFR antibodies such as cetuximab were designed to bind to the extracellular domain of the EGFR and block activation of EGFR downstream signaling  
In contrast, small-molecule TKIs such as gefitinib or erlotinib compete with ATP for binding to the intracellular catalytic domain of the EGFR tyrosine               kinase  and thus prevent EGFR autophosphorylation and downstream signaling....       
 

Ab806 is in the first category was created to address EGFRvIII.  "Ab806 is remarkably effective in blocking EGFRvIII signaling and inducing tumor cell apoptosis, resulting in dramatic tumor regression in the EGFRvIII-driven murine lung cancers."  Li (75)

CONCLUSION 

Non-smokers and light former smokers frequently have the EGFR damage that predicts response.  For this group, Tarceva is an important treatment which frequently achieves a partial response.  Outside this group, the use of Tarceva is controversial; some may argue that the prevalence of EGFR signalling in many lung tumors and limited side effects, mean that Tarceva can be a helpful drug, particularly with chemotherapy.  Others argue studies show that response is associated with the EGFR damage  and that the perception of stabilized disease may be unrelated and that other treatments make more sense.  Tarceva's side effects are limited particularly when contrasted with chemotherapy drugs which impact many types of dividing cells causing more substantial changes.  EGFR testing makes sense to confirm that the patient has the type of disease which is likely to respond to Tarceva.

Unfortunately, many who respond to Tarceva develop second areas of genetic damage allowing signalling at EGFR.  The possibility of this should be closely monitored with consideration given to cell samples to monitor EGFR.  Where a second area of EGFR damage is identified. the patient can consider pan-inhibitors which permanently suppress EGFR functioning.  He may also wish to consider the use of other drugs to inhibit EGFR signalling.  Dowell (71).  Another work showed how  "binding of erlotinib to wild-type (normal) EGFR, whereas Panel B shows how the T790M mutation leads to steric hindrance of erlotinib binding owing to the presence of the bulkier methionine side chain (orange) in the ATP-kinase–binding pocket."

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 (portions of this article were excerpted from the book Lung Cancer and Mesothelioma,  with added material based on recent research).  
for questions about this article, email howian@aol.com.  This article is not intended to provide medical advice or treatment. keywords  Tarceva, lung cancer, epidermal growth factor receptor, Iressa, non-smoker's lung cancer,  EGFR, EGF, Tarceva and lung cancer,  treatments for lung cancer).  

Dictionary of Terms and Science

ATP  The high-energy medium in the cell.  ATP has " high-energy phosphate bonds and is used to transport energy to cells for biochemical processes, including muscle contraction and enzymatic metabolism."   The term is short for Adenosine triphosphate,

Epidermal Growth Factor Receptor EGFR is a member of the ErbB family receptors, a subfamily of four closely related receptor tyrosine kinases:  Its activation has been associated with various carcinogenic processes. EGFR activated by binding of its ligands by EGF or other growth factors. 

Epidermal growth factor receptor is "A protein found on the surface of cells to which epidermal growth factor (EGF) binds. When EGF attaches to EGFR, it activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. EGFR is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively in the presence of EGF.  The drug Iressa attaches to EGFR and thereby inhibits the attachment of EGF and stops cell division. The gene for EGFR is on chromosome 7p12.3-p12.1. The EGFR molecule has 3 regions -- one projects outside the cell and contains the site for binding EGF; the second is embedded in the cell membrane; and the third projects into the cytoplasm of the cell's interior. EGFR is a kinase that attaches phosphate groups to tyrosine residues in proteins. EGFR is also known confusingly as ErbB1, ErbB, oncogene ErbB, and HER1." www.medterms.com

"The binding of the ligand stimulates the intrinsic protein-tyrosine kinase activity of EGFR which initiates a signal transduction cascade, principally involving the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation. The kinase activity can also result in autophosphorylation of five tyrosine residues in the C-terminal domain of EGFR. Autophosphorylation elicits downstream activation and signaling events of other proteins that are often distinct from those activated by the kinase domain of EGFR."   Answers.com -epidermal growth factor receptor

Erbitux Erbitux is a monoclonal antibody and its mode of action has been distinguished from Tarceva and Iressa. "Two classes of anti-EGFR agents are currently approved for the treatment of patients with cancer: cetuximab, a monoclonal antibody directed at the extracellular domain of the receptor, and gefitinib and erlotinib, oral, low-molecular-weight (MW), adenosine triphosphate (ATP)-competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR monoclonal antibodies have demonstrated activity in the therapy of advanced colorectal carcinoma and in a variety of epithelial tumor types, including head and neck cancer and non-small cell lung cancer (NSCLC). "  Mendelsohn,Epidermal growth factor receptor targeting in cancer Semin Oncol. 2006 Aug;33(4):369-85.

Phosphyation  The chemical process in which a phosphate group is added to an organic molecule. In eukaryotic cells,  "protein phosphorylation is probably the most important regulatory event.  Many enzymes and receptors are switched "on" or "off" by phosphorylation and dephosphorylation. Phosphorylation is catalyzed by various specific protein kinases,"    Within a protein, phosphorylation can occur on several amino acids. Phosphorylation on serine is the most common, followed by threonine.  Answers.com Phosphylation.

Tarceva (Erlonitib) Tarceva "is one of a new group of drugs that target tiny flaws in the cell's communication system. Many cells have receptors on their surfaces for epidural growth factor (EGF), which is a protein produced by the body which induces growth and multiplication of cells. This protein causes an enzyme called tyrosine kinase to become active within the cells. Erlotinib blocks the cancer cell from getting the message that tells the cell to grow and divide, and the cells stop growing."  Answers.com Erlonitib.

Tarceva competitively binds to EGFR  and therefore prevents ligand-binding which can initiate cancerous signalling.  Studies indicate it is most effective on non-smokers and light smokers whose tumors have a specific EGFR tyrosine kinase mutation.  Lynch, Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib, Volume 350:2129-2139, May 20, 2004

Tyrosine Kinase  "A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). This usually results in a functional change of the target protein (substrate), by changing enzyme activity, cellular location or association with other proteins. Up to 30% of all proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction, the transmission of signals within the cell. The human genome contains about 500 protein kinase genes; they constitute about 2% of all eukaryotic genes."  Wikipedia, protein kinase

There are two types of tyrosine kinases, cytoplasmic kinases  and receptor tyrosine kinases.  EGFR is a receptor tyrosine kinas.   Receptors lie on the surface of these cells, hence the term, cell-surface receptor, and connect with various growth factors. . 

Its structure is
1) an extracellular domain domains which is involved in recognizing and binding the ligands that are able to activate the receptor,
2)membrame,
3) the intracellular domain where the enzymatic activity of the tyrosine kinase that is able to phosphorylate tyrosine residues occurs.

A reaction is initiated by binding at the ligand-binding level, which leads to phosphylation chemical changes in the kinase region resulting in signaling to other cells.     "Binding of a ligand to this type of receptor stimulates the receptor's intrinsic protein-tyrosine kinase activity, which subsequently stimulates a signal-transduction cascade."  Lodish,Mollecular Cell Biology  872 (4th ed. 1999).    " A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein."  Tyrosine Kinase, Wikipedia.

Questions or comments are welcome, email howian@aol.com

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