Content area
Full Text
Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
Protein kinase activation by somatic mutation or chromosomal alteration is a common mechanism of tumorigenesis (1). Inhibition of activated protein kinases through the use of targeted small molecule drugs or antibody-based strategies has emerged as an effective approach to cancer therapy (2-4). Recently, systematic analysis of kinase genes has identified mutations of the protein serine-threonine kinase gene BRAF in melanoma and other human cancers (5) and of multiple tyrosine kinase genes and the phosphatidylinositol 3-kinase p110[alpha] catalytic subunit gene PIK3CA in human colorectal carcinoma (6, 7).
Lung carcinoma is the leading cause of cancer deaths in the United States and worldwide for both men and women (8). Chemotherapy for non-small cell lung carcinoma (NSCLC), which accounts for approximately 85% of lung cancer cases, remains marginally effective (9).
Recently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib (Iressa), was approved in Japan and the United States for the treatment of NSCLC. The original rationale for its use was the observation that EGFR is more abundantly expressed in lung carcinoma tissue than in adjacent normal lung (10). However, EGFR expression as detected by immunohistochemistry is not an effective predictor of response to gefitinib (11).
Clinical trials have revealed significant variability in the response to gefitinib, with higher responses seen in Japanese patients than in a predominantly European-derived population (27.5% versus 10.4%, in a multi-institutional phase II trial) (12). In the United States, partial clinical responses to gefitinib have been observed most frequently in women, in nonsmokers, and in patients with adenocarcinomas (13-15).
To determine whether mutation of receptor tyrosine...