LAPATINIB (HKI 272) AND LUNG CANCER

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

1.0 Overview of HKI 272

Lapatinib, HKI 272, appeared with much promise as a so-called irreversible inhibitor.  Tarceva is an effective drug with lung cancer patients who are EGFR positive.  After responding to Tarceva, many of these patients develop resistance from what is called the T790 mutation.  Laboratory tests indicated Lapatinib was effective in suppressing the mutation.  However, the cell studies have not translated into success in human trials, and today scientists are examining its use with other drugs.

2.0 Mechanism

HKI-272, trade name Papatinib is called an irreversible inhibitor.  The term irreversible refers to the drug's mode of action; one can apparently
terminate the drug without serious ill effects.  It attacks both EGFR and HER2, two tyrosine kinases associated with lung cancer. 

The human body has a complex system of signaling between cells and duplication of genes is a normal part of this process.  Duplication of genes is necessary for growth, repair of damaged cells and other functions.   Proteins called growth factors signal other cells to initiate replication but malfunctions in these growth factors are a part of cancer, as they prompt excessive duplication.  "Growth factors — such as human epidermal growth factor — that bind to cell-surface receptors are important regulators of normal cell proliferation and survival. Dysregulation of signal transduction pathways, including overexpression of growth factor receptors, is one of the fundamental elements contributing to the growth and progression of many solid tumors."  Genentech (72).

Epidermal Growth Factor (EGF) plays a role in normal human development helping to repair damaged tissue and develop lungs in fetuses.  When glands associated with the epidermal growth factor were removed from pregnant mice, scientists found increased mortality and reduction of milk production.  To initiate cell reproduction, a growth factor links with an associated receptor, like a lock and key.  EGF links with EGFR, the epidermal growth factor receptor. 
In recent years, the receptor EGFR  has become the target of new drugs. 

“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).   

3. Combinations

Scientists are looking at whether combined treatment could be effective with the drugs Erbitux or Rapamycin.

A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC. Kim (3) See also Li (32)

The type of tumor may be important. Mouse model studies further revealed that HKI-272 was efficacious against alveolar but not bronchial tumors, and HKI-272 resistance in bronchial tumors was overcome by the addition of rapamycin.

 

REFERENCES HKI 272 and Pan Inhibitors

J. V. Heymach,
Epidermal growth factor receptor inhibitors in development for the
treatment of non-small cell lung cancer.
Clin. Cancer Res., July 15, 2006; 12(14): 4441s - 4445s.


T. Shimamura,
Non-Small-Cell Lung Cancer and Ba/F3 Transformed Cells Harboring the ERBB2
G776insV_G/C Mutation Are Sensitive to the Dual-Specific Epidermal Growth
Factor Receptor and ERBB2 Inhibitor HKI-272.
Cancer Res., July 1, 2006; 66(13): 6487 - 6491.


J. Baselga
Is There a Role for the Irreversible Epidermal Growth Factor Receptor
Inhibitor EKB-569 in the Treatment of Cancer? A Mutation-Driven Question
J. Clin. Oncol., May 20, 2006; 24(15): 2225 - 2226.


H. Ji, X. Zhao,
Epidermal growth factor receptor variant III mutations in lung
tumorigenesis and sensitivity to tyrosine kinase inhibitors
PNAS, May 16, 2006; 103(20): 7817 - 7822.


E. L. Kwak,
Irreversible inhibitors of the EGF receptor may circumvent acquired
resistance to gefitinib
PNAS, May 24, 2005; 102(21): 7665 - 7670.

(overall references on EGFR and HKI-272)

1. FDA. Advisory Meeting Document for the Use of Iressa, FDA. Gov.
2. Tartora, A novel approach in the treatment of cancer: targeting the Epidermal Growth Factor Receptor, Clin Cancer Res 2001 Oct;7(10):2958-70
3. Pass, Lung Cancer, 186 Lippincott, 2000) citing Tateshi, Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung, Cancer Res 1990; 50: 7077.
4. Cox, Matrix metalloproteinases 9 and the epidermal growth factor signal pathway in operable non-small cell lung cancer, Clin Cancer Res 2000 Jun;6(6):2349-55
5. Ohsaki, Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression, Oncol Rep 2000 May-Jun;7(3):603-7
6. Kostyleva, EFR-like peptides and their receptors as prognostic factors for the survival of patients with non-small cell lung cancer, Vopr Onkol 1999;45(6):617-22.
7. Ferraro, New Ammunition in Cancer War, New York Post 5/20/01, p. 28.
8. Natale, ZD1839 (Iressa): What's in it for the Patient, The Oncologist, Vol. 7, Suppl 4, 25-30, August 15, 2002
9. Oncology 1997 Mar-Apr;54(2):134-40
10. Ferry, Intermittent Oral ZD1839 (Iressa), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), Shows Evidence of Good Tolerability and Activity: Final Results from a Phase I Study.” www. asco.org. 2.
11. Uejima, A phase I intermittent dose escalation trial of ZD1839 (Iressa™™) in Japanese patients with solid tumors. Annals of Oncology, Vol 11, Suppl.4 October 2000, page 110
12. Fortunate, Inhibition of Growth Factor Production and Angiogenesis in Human Cancer Cells by ZD1839 (Iressa), a Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Clin Cancer Res 2001 May;7(5):1459_1465
13. See Ciardiello, EGFR-Targeted Agents Potentiate the Antitumor Activity of Chemotherapy and Radiotherapy,Signal, Volume 2, number 2, (2001) 4.6
14. Ciardiello, EGFR-Targeted Agents Potentiate the Antitumor Activity of Chemotherapy and Radiotherapy,Signal, Volume 2, number 2, (2001)
15. Hainsworth, NSCLC: An Overview of Current and Upcoming Trials, 2nd Int. Lung Cancer Congress, July 18, 4
16. Sololer, Phase II Trial of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor OSI-774, Following Platinum-Based Chemotherapy, in Patients (pts) with Advanced, EGFR-Expressing, Non-Small Cell Lung Cancer (NSCLC).2001, www.Medscape.com
17. Hidalso Phase I and pharmacological study of OSI-774, an epidermal growth factor receptor tyrosine kinase.
18. Lung Cancer, Oncologist 2001; 6 (5): 407-14
19. www.astrazeneca-us.com/news/article.asp?file
20. Zhonghua, The Growth Inhibition of anti-EGF receptor monoclonal antibody to human lung adenocarcinoma cells, Jie He He Hu Xi Za Zhi 1998 Apr; 21(4):233-5.
22. Inoue, Severe Acute Interstitial Pneumonia and Gefitinib (Iressa), Lancet 2003 Jan 11;361(9352):137-9
23. Janne, Inhibition of epidermal growth factor receptor signaling in malignant pleural mesothelioma, Cancer Res 2002 Sep 15;62(18):5242-7.
24.Baselga, Why the Epidermal Growth Factor Receptor? The Rationale for Cancer Therapy, The Oncologist, Vol. 7, Suppl 4, 2-8, August 15, 2002 (currently available online at no cost).
25. Baselga, Epidermal Growth Factor: A Rational Target for Cancer Therapy, American Society of Clinical Oncology )ASCO) (2003) (presentation available online at www. Egfr-info.com
26. Normanno, Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth, Annals of Oncology 13:65-72, 2002.
27. Ranson, ZD1839 (IressaTM): For More Than Just Non-Small Cell Lung Cancer, The Oncologist, Vol. 7, Suppl 4, 16-24, August 15, 2002
28. Slamon, Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2, New England Journal of Me dicine, Volume 344:783-792, March 15, 2001, number 11.
29. HER-2 diagnostics, Magy Onkol 2002;46(1):11-5 (2002).
30. Potti, Predictive role of HER-2/neu overexpression and clinical features at initial presentation in patients with extensive stage small cell lung carcinoma,  Lung Cancer 2002 Jun;36(3):257-61
31. www.NCI.org.
32.  Steinberg, Closing in on Multiple Cancer Targets, The Scientist 16[7]:29, Apr. 1, 2002. 
33.  A phase 1 clinical and pharmacokinetic study of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, in patients with advanced solid tumors, www.asco.org (2002). 
34. Inhibitors of erbB-1 kinase, Expert Opinion on Therapeutic Patents, 2002, vol. 12, no. 12, pp. 1903 - 1907
35.  Allen, Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer, Semin Oncol 2002 Jun;29(3 Suppl 11):11-21
36. www.brittanica.com Growth Factors. 
37. Lipton, Mollecular Profiling of an Individual Patient's Tumor: is this the Future of Cancer Treatment,
Signal, Volume 3, Issue 4, 2-3, 21, available online at www.egfr-info.com
38. Hynes, Tyrosine Kinase Signalling in Breast Cancer, Breast Cancer Res 2000, 2:154-157, http://breast-cancer-research.com/content/2/3/154.  
39. Satoh, Regulation of the Expression of Epidermal Growth Factor Receptor MRNA..., 
Yomago Acta medica 1997;40:133-36 http://lib.med.tottori-u.ac.jp/yam/bef_41/yam40(3)/sato.pdf
40. Albanell, Unraveling Resistance to Trastuzumab (Herceptin): Insulin-Like Growth Factor-I Receptor, a New Suspect, Journal of the National Cancer Institute, Vol. 93, No. 24, 1830-1832, December 19, 2001
41. Cappuzzo, Gefitinib in Pretreated Non-Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC, J Clin Oncol. 2003 Jul 15;21(14):2658-63.
42. Dancey, Targeting epidermal growth factor receptor--are we missing the mark, Lancet. 2003 Jul 5;362(9377): 62-4.
43. Talbot, The Epidermal Growth Factor (EGF) Family, (Gropep advertisement for EGF gene products). 
44. Janmaat, Response to Epidermal Growth Factor Receptor Inhibitors in Non-Small Cell Lung Cancer Cells: Limited Antiproliferative Effects and Absence of Apoptosis Associated with Persistent Activity of Extracellular Signal-regulated Kinase or Akt Kinase Pathways. Clin Cancer Res. 2003 Jun;9(6):2316-26.
45.  Funokuora, Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer, J Clin Oncol. 2003 Jun 15;21(12):2237-46. Epub 2003 May 14
46. Bianco, Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors., Oncogene. 2003 May 8;22(18):2812-22.
47. www.fda.gov, Center for Drug Evaluation and Research Approval Package for Application Number 21-399., Medical Review  
48. www.fda.gov, Center for Drug Evaluation and Research Approval Package for Application Number 21-399, Statistical Evaluation.  
49. Klein, Effect of tyrosine kinase inhibition on surfactant protein A gene expression during human lung development, Am J Physiol Lung Cell Mol Physiol 274: L542-L551, 1998
50. World Conference on Lung Cancer, webcast, Mollecular Targeted Lung Cancer  1 Epdimeral Growth Factor Tyrosine Kinase Inhibitors. 
51. Miller, Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer,. J. Clin Oncol. 2004 Mar 15;22(6):1103-9.
52. Gelibter, Clinically meaningful response to the EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in non small cell lung cancer, J Exp Clin Cancer Res. 2003 Sep;22(3):481-5.
53. West, Gefitinib (ZD1839) therapy for advanced bronchioloalveolar lung cancer (BAC): Southwest Oncology Group (SWOG) Study S0126, Abstract 7014, 2004 Asco Annual Meeting, asco.com.
54. Tortora, Combination of a Selective Cyclooxygenase-2 Inhibitor with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 and Protein Kinase A Antisense Causes Cooperative Antitumor and Antiangiogenic Effect, Clinical Cancer Research Vol. 9, 1566-1572, April 2003
55. Lynch, T. J.  Specific Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib. The New England Journal of Medicine (online April 29, 2004).
56. Paez, J. G.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science (Published online April 29, 2004)
57.  Riely, Clinical Course of Patients with Non–Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib
58. Chou, Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer, Clin Cancer Res. 2005 May 15;11(10):3750-7.                                                             
59. Shigematu, Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers
Journal of the National Cancer Institute, Vol. 97, No. 5, 339-346, March 2, 2005
60. Takano, Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer, Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 6829-6837
61. McKinnie, Tarceva v. Iressa,...www.frost.com/prod/servlet/market-insight-top.pag?docid=29429716
62. Press Release, Why Some Cancers Stop Responding to Tarceva and Iressa,  www.sciencedaily.com/releases/2005/02/050223164218.htm
63.  Molecular Test Helps Guide Treatment for Lung Cancer, www.partners.org/Pharma_Testing_Popup.html
64.  Oda, A comprehensive pathway map of epidermal growth factor receptor signaling, Molecular Systems Biology. www.nature.com (available online at no charge)
65. Yokoyama, EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci. 2006 Aug;97(8):753-9.
66. Dudek, Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer, Lung Cancer. 2006 Jan;51(1):89-96. Epub 2005 Nov 14.
67. Amler, Predicting clinical benefit in non-small-cell lung cancer patients treated with epidermal growth factor tyrosine kinase inhibitors, Cold Spring Harb Symp Quant Biol. 2005;70:483-8.
68.  Pao, Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain, PLoS Med 2005 2(3):
69. Sasaki, EGFR and erbB2 mutation status in Japanese lung cancer patients, Int J Cancer. 2006 Jan 1;118(1):180-4.
70. Hsieh, Female Sex and Bronchioloalveolar Pathologic Subtype Predict EGFR Mutations in Non-small Cell Lung Cancer, (Chest. 2005;128:317-321.)
71. Dowell, Chasing Mutations in the Epidermal Growth Factor in Lung Cancer, NEJM, Volume 352:830-832 February 24, 2005 Number 8.  (available online at no charge)
72. Kobayashi, EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib, Volume 352:786-792 February 24, 2005 Number 8 (available online at no charge)
73. Kwak, Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib, PNAS | May 24, 2005 | vol. 102 | no. 21 | 7665-7670 (available online at no charge)
74. Ji, Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors
PNAS 2006 103: 7817-7822;
75. Li, Therapeutic anti-EGFR antibody 806 generates responses in murine de novo EGFR mutant–dependent lung carcinomas, J. Clin. Invest. 117:346-352 (2007).
76. Wikstrand Monoclonal Antibodies Against EGFR vii are Tumor Specific ...55 Cancer Research 3140-48, 1995, 
77. Okamato, Expression of constitutively activated EGFRvIII in non-small cell lung cancer, Cancer Science 2003 Jan;94(1):50-6.
78. Rabintran, Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase, Cancer Research 64, 3958-3965, June 1, 2004
79. www. biooncology.com, Her signaling. (Genentech website)

Clinical Trial Listing for HKI 272

1. Sloan Kettering New York City

 (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

$23.95  Order from www.xlibris.com. or www.amazon.com     Search for:  (keywords, Tarceva, lung cancer, epidermal growth factor receptor, Iressa, HKI 272, non-smoker's lung cancer, EGFR, EGF, T790m mutation, Tarceva treatment, second mutation, HKI 272  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).ite keywords, Tarceva, lung cancer, epidermal growth factor receptor, Iressa, non-smoker's lung cancer, EGFR, EGF, tarceva treatment, second mutation, Tarceva and lung cancer, treatment for lung cancer, EGFR, epidermal growth factor, egfr antibody, egfr inhibitor,