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.
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).
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.
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Non-Small-Cell Lung Cancer and Ba/F3 Transformed Cells Harboring the ERBB2
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E. L. Kwak,
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Clinical Trial Listing for HKI 272
1. Sloan Kettering New York City
A Phase II Study of HKI-272 in Patients with Advanced Non-Small Cell Lung Cancer
(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 firstname.lastname@example.org. 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 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.
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,
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 email@example.com
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