Thao P. Dang M.D.

Lay Description

With a better understanding of how cancer is caused at a molecular level, we are able to use treatments that specifically target proteins that are fundamental in the development or progression of cancer cells. One such target is the epidermal growth factor receptor (EGFR), one of a family of cell surface molecules that functions to transmit cell growth signals from outside the cell to the nucleus. This receptor is over-active (over-expressed), in 60-80% of human lung cancers, and this is associated with poor survival and resistance to chemotherapy or radiation therapy. Several drugs that block EGFR signaling are now being tested in patients. One such drug is gefitinib, a small molecule that penetrates the cell membrane and blocks epidermal growth factor receptor activation on the inside, at a point in the pathway where it inhibits an enzyme called tyrosine kinase. Gefitinib is therefore termed an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). Preclinical studies in models have shown that using this gefitinib inhibits the growth of cancer cells and in some cases leads to shrinkage of tumors. Although up to 80% of lung cancers express the epidermal growth factor receptor, fewer than 20% of patients will respond to treatment with gefitinib. Paradoxically, when this drug is given to patients having tumors that exhibit the lowest rate of EGFR expression, such as bronchioalveolar carcinoma, the highest rate of response is seen, up to 30% in some cases.

This study is designed to explore the question of how lung cancer cells are able to escape blockage of the epidermal growth factor receptor signaling pathway. This will help to identify patients with tumors that are resistant to treatment by drugs such as gefitinib. This will prevent treating these patients with an ineffective drug that has potentially significant side effects.

We have identified three proteins that when altered can render patients resistant to therapy. One such protein is an abnormal form of the EGFR, known as EGFRvIII (or EGFR variant III). This abnormal protein will become activated by itself without signals from outside the cell. Another protein, K-ras, when mutated will also allow this pathway to activate unchecked. Notch3 is another cell surface receptor similar to the epidermal growth factor receptor, but signals through a different set of proteins. This protein is also important in the survival and maturation of normal cells, but when abnormally activated can play an important role in the development of cancer. We observed that when Notch3 is highly expressed, it can activate proteins that are also activated by EGFR but without requiring signaling from EGFR itself. Thus, EGFRvIII, K-ras, and Notch3 each promote survival of cancer cells independent of signaling by EGFR. We hypothesize that patients identified having any of these three proteins will not respond to therapy with EGFR-TKI such as gefitinib and can be saved from non-efficacious, toxic and expensive treatment.

Scientific Abstract

Better understanding of the intracellular signaling process important in cellular transformation and tumor progression has allowed the identification of many potential therapeutic targets. The c-erB family of receptors regulates many important cellular functions and survival, including proliferation in response to growth factors and mitogens. Epidermal growth factor receptor (EGFR) or c-erB-1 is expressed in 60-80% of lung cancers and correlates with a worse prognosis as well as resistance to chemotherapy and radiation therapy. Many therapeutics targeting EGFR are being tested in clinical trials. Gefitinib (AstraZeneca) is a small molecule targeting the tyrosine kinase enzyme within the EGFR signaling pathway. An object response rate of 20% was seen in phase II trials, an encouraging result since many patients were previously treated with one or two chemotherapy treatments. Interestingly, there is no correlation between EGFR expression and response to therapy. This suggests that mutations in either the receptor or downstream effector molecules result in the activation of EGFR signaling but at the same time confer resistance to EGFR tyrosine kinase inhibitors. Bronchioalveolar carcinoma (BAC) has the highest response rate to EGFR-TKI (38%) despite a lower rate of EGFR expression when compared to lung tumors with squamous histology.

Epidermal growth factor signals through its receptor (EGFR). Binding of ligand results in autophosphorylation and activates both the MAPK and the Akt cascades. Point mutations in the K-ras gene, a downstream signaling molecule of EGFR pathway, and a mutation in the EGFR receptor known as the EGFRvIII result in constitutive or ligand independent activation of the pathway. Another potential mechanism of gefitinib involves Notch3. The Notch family is important in cell fate determination and recently has been demonstrated to also be important in tumorigenesis. We have shown that Notch3 is expressed in approximately 40% of lung cancers. Constitutive activation of Notch3 results in phosphorylation of MAPK (ERK1/ERK2), and this activation is independent of EGFR signaling.

We will measure levels of K-ras mutation, EGFRvIII and Notch3 expression using tumors from a clinical database of patients treated with gefitinib. We will correlate these findings with response to treatment. This will allow identification of gefitinib "sensitive" tumors and thereby prevent patients with resistant tumors from being subjected to a nonefficacious and potentially toxic treatment.