Craig W. Lindsley and Ashley L. Thomas Pages 62 - 62 ( 1 )
Overcoming Resistance. Over four years ago, on May 2, 2003, the FDA approved Iressa™ (gefitinib) by AstraZeneca for the treatment of non-small cell lung cancer (NSCLC) in patients that failed to respond to two other types of chemotherapy. The potential therapeutic benefit of Iressa™, a once-daily tablet, was obvious, as the drug elicited an objective response and was well-tolerated in Phase II trials. The subsequent Phase III clinical trial, however, failed to prove that patients taking Iressa™ survived longer than those taking placebo. Due to these results, on June 17, 2005, the FDA limited the use of Iressa™ to patients who were currently benefiting or had previously benefited from the drug and patients that had formerly been enrolled in clinical trials. Importantly, although clinical trials of Iressa™ did not demonstrate a survival benefit for the overall patient population, the study showed a statistically significant increase in survival for patients of Asian origin and patients who had never smoked . The epidermal growth factor receptor (EGFR) performs a critical role in cellular proliferation, differentiation and survival. Aberrant EGF-EGFR signaling, as in the case of mutations, leads to overexpression of wild-type EGFR – a hallmark of a broad range of cancers, including lung, breast and colon carcinomas . Iressa™, a quinazoline derivative, is a tyrosine kinase inhibitor (TKI) that selectively targets EGFR. Despite the initial response to the drug in the majority of NSCLCs, most of the tumors eventually develop resistance to Iressa™. A secondary mutation in the EGFR gene is responsible for resistance in approximately half of these cases, but the cause of resistance in the remaining cancer cells is still being investigated. A recent study (Br. J. Cancer 2007, 97, 1560-1566) determined that classical mutations in the EGFR TK domain (exons 18, 19 and 21), but not other mutations, are associated with the clinical outcome in – treated patients with NSCLC . A recent study by Dr. Jeffrey A. Engelman et al. (Science 2007, 316, 1039-1043) suggests that amplification of the MET oncogene may be another mechanism that leads to resistance, indicating combination therapy with MET kinase inhibitors as a possible solution . Even if Iressa™ does not prove to be the cancer therapeutic that was hoped for, the molecule may serve as the precursor to a new effective anticancer agent. Tarceva™ (erlotinib), a joint product of Genentech, Inc. and OSI Pharmaceuticals, Inc., is a derivative of Iressa™ and another EGFR tyrosine kinase inhibitor that is currently in Phase III clinical trials. Research is also being conducted to synthesize more analogues of Iressa™; Professor Jean-Pierre Henichart et al. synthesized 23 Iressa™ derivatives, many of which decreased proliferation and induced apoptosis in human prostate cancer cells. The future of Iressa™ will be determined by further evaluation of the drugs effectiveness in subgroups, understanding of the cancer cells resistance mechanisms, and novel therapies to overcome that resistance. REFERENCES  For detailed information and press releases describing Iressa™, see www.astrazeneca.com.  Cragg, M.S.; Kuroda, J.; Puthalakath, H.; Huang, D.C.S.; Strasser, A. PloS Medicine 2007, 4, 1681-1690.  Pallis, A.G.; Kalikaki, A.; Souglakos,, Molecule, of, the, Month
Vanderbilt University, Vanderbilt University Medical Center Department of Pharmacology and Chemistry Robinson Research Buliding 804 Nashville, TN 37232-6600, USA.