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. Bronchioloalveolar 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.