HKI 272 AND LUNG CANCER

(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).  

1.0 Overview and The Epidermal Growth Factor Receptor

HKI  272 is a promising new drug which works by suppressing EGFR and Erb2 signaling associated with 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 months, 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).   

"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)  

2.0 Problems with Conventional EGFR Drugs Iressa and Tarceva Clinical Trials

Iressa and Tarceva are drugs which target the EGFR.  Specifically both are tyrosine kinase inhibitors because they target the tyrosine kinase portion of the EGFR. Two problems or limitations have been seen with these drugs.  Tarceva and Iressa were shown to have impressive results with a particular subgroup of patients.  These were non-smokers (or very light former smokers) with adenocarcinoma or BAC and a specific type of damage to the tyrosine kinase area of the EGFR.   Lynch (55).  However, this comprises only about 10% of the lung cancer patients. 

Secondly, many of these patients have impressive initial responses.  There are reports even of complete responses among stage 4 patients and eliminate of metastases in various parts of the body.  However, after the initial impressive response, the tumors of the patients have relapses.  Scientists found the body developed a new mutation at  T790M which was Tarceva resistant. 

3.0 Rationale for HKI 272

HKI 272 is stronger drug than Tarceva.   It holds the promise of more impressive results, but the risk of increased side effects. HKI 272 is called an irreversible pan-inhibitor, though what that means is unclear.  Irreversible seems to indicate that the drug permanently inhibits at least some EGFR signaling. This is the benefit of the drug- when the body develops the T790M mutation to sidestep the effect of Tarceva, HKI 272 appears to continue suppression of EGFR signalling. 

EGFR is part of the family or ERB receptors.  HKI-272 appears to suppress not only EGFR signalling but Erb-2 signalling which has been associated with various cancers.  Cross-talk or cross-signalling is part of receptor functioning but HKI-272 and other pan-inhibitors are designed to suppress this.  
  

4.0 Cell Studies with HKI 272 and Pan-inhibitors

One study found pan-inhibitor HKI 272 effective with tumor cells in a laboratory setting.      "HKI-272 dramatically inhibits the growth of EGFRvIII-transformed cells in vitro and tumor growth in vivo."  Ji (74).

"HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal     growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G₁-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule." Rabintran" (78). 

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 (74)

"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 (71)

 5.0 Implications for Treatment  

Human studies are needed to determine side effects.  There are several potential areas of treatment.

       5.01 T790M responders

A subgroup with an EGFR tyrosine kinase mutation responded well to Tarceva treatment (Lynch 55) but developed a second  T790M mutation.  HKI 272 is effective in suppressing this mutation, at least in cell studies.  The drug has a therapeutic basis for this subgroup.

Secondly, HKI 272 could be tested on a wide variety of lung cancer patients.  The above group's tumors are EGFR-driven, but others may have an EGFR or Erb-2 component. 

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.

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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,