Targeted Lung Cancer Therapy: What Have We Learned from Gefitinib?

EDITORIAL

Targeted lung cancer therapy: what have we learned from gefitinib?

showed significant clinical benefit in patients with ‘Gefitinib in lung cancer and chronic myelogenous leukemia (CML) with posi- imatinib in CML mark the beginning tive Philadelphia chromosome and the BCR-ABL of a new era for cancer treatment fusion gene [2,3]. Imatinib induces both hematolog- – targeted cancer therapy.’ ical and molecular remission in CML patients [3]. This is the first drug that specifically targets a regulatory molecule within the cancer cells leading to Lung cancer is the leading killer of all cancer clinical remission of cancer patients. Subsequently, patients, accounting for 28% of all cancer gefitinib (Iressa®, ZD1839) from AstraZeneca, was deaths. Lung cancer is classified histologically as developed for NSCLC [4–6] using a very similar small cell lung cancer (SCLC) and non-small cell principle and technology to imatinib. Gefitinib is a lung cancer (NSCLC) including adenocarci- synthetic small organic molecule targeting the noma, squamous carcinoma and other subtypes. intracytoplasmic domain of the epidermal growth SCLC represents approximately 20% of lung factor receptor (EGFR) which is expressed in a vari- cancers, and NSCLC represents the remaining ety of normal human tissues and cancers [7]. The 80%. Based on cancer statistics from the Ameri- binding of gefitinib to EGFR prevents intracyto- can Cancer Society, there were 175,000 new plasmic signaling by inhibiting intrinsic tyrosine Peilin Zhang† & cases of lung cancer in the USA and approxi- kinase activity, thus blocking the growth-promot- John Rogers mately 165,000 lung cancer deaths in 2004. ing effect of the EGFR (tumor cell proliferation). †Author for correspondence Unlike other common cancer types, there Based on cell culture studies, gefitinib would be Putnam General Hospital appears to be a tight correlation between lung potentially useful for cancers with high expression Laboratory, 1400 Hospital Drive, Hurricane, cancer incidence and death, indicating the poor of EGFR, such as squamous cell carcinoma of the WV 25526, USA outcome regardless of treatment modalities. lung, squamous cell carcinoma of the head and Tel: +1 304 757 1768 Traditionally, early stage NSCLC (Stage I, II and neck, glioblastoma multiforme and others [4,7]. Ini- Fax: +1 304 757 1736 IIIA) has been treated with surgical resection when tial clinical data suggests otherwise. Multicenter Peilin.Zhang@hcahealthcare .com possible. Adjuvant chemotherapy is recommended clinical trials on NSCLC, including squamous cell after surgery. Locally advanced NSCLC (some carcinoma and adenocarcinoma ,showed that only stage IIIA and stage IIIB) is generally treated with a small fraction of NSCLC patients responded to radiation combined with chemotherapy. Patients gefitinib with tumor shrinkage [4]. Many of those with distant spread (stage IV) receive palliative responding to the drug were non-smoking women chemotherapy, usually consisting of one cytotoxic with adenocarcinoma, especially with bronchioal- drug such as paclitaxel, doceptaxel or gemcitabine veolar features. Responding patients represent combined with a platinum derivative. There have approximately 10% of the total of NSCLC popula- been a number of regimens evaluated in clinical tri- tion. Following this clinical observation, two inde- als without demonstration of one clearly superior pendent groups simultaneously discovered the treatment regimen in regard to patient survival [1]. underlying molecular mechanism by which gefit- Clearly, new treatment approaches are needed to inib exerts its function. They selected the gefitinib- improve patient survival in lung cancer. responsive patients, extracted the genomic DNA There are emerging products based upon the from patient tumor samples and sequenced the recent advances of molecular biology of human entire EGFR gene. Remarkably, clusters of EGFR cancers. Unlike cytotoxic chemotherapy drugs, mutations were uncovered within exons 19 to 21 of these new agents target molecular signaling path- the EGFR gene from the majority of gefitinib- ways within the cancer cells and show promise in a responsive tumors, but not from gefitinib-resistant variety of cancers. Imatinib (STI-571, Gleevec®, tumors. Gene mutations were found within the Glivec®, Novartis Pharma), the first of the tar- activation loop of the tyrosine kinase domain of geted agents, is an inhibitor of cytoplasmic c-Abl EGFR. The most common mutations were small kinase approved by the US Food and Drug in-frame deletions or amino acid substitutions Future Drugs Ltd Administration (FDA) in 2001. Imatinib has within this region [8,9]. Furthermore, the mutations

from the gefitinib-responsive tumors were hetero- From a histopathology point of view, human zygous, suggesting a gain-of-function mutation. solid tumors are heterogeneous in nature with sig- Mutations of this activation loop of the EGFR nificant variations in morphology, growth and sequence rendered the receptor significantly more differentiation among the same histologic types of sensitive to ligand binding and cellular signaling tumor. At the molecular levels, although many function [8–10]. genes were discovered to be mutated in the tumors, the key regulatory gene(s) which serve as ‘Lung cancer is the leading killer of all a driving force for tumor growth/antiapoptosis in cancer patients accounting for 28% of all about 90% lung cancers remain to be discovered. cancer deaths.’ Gefitinib in lung cancer and imatinib in CML mark the beginning of a new era for cancer treat- Interestingly, further work demonstrated that ment – targeted cancer therapy. This is an exciting these mutations activated downstream targets such time for close collaboration between basic scien- as AKT and signal transducers and activators of tists and clinical oncologists. An optimal interdis- transcription (STAT) signaling pathways, promot- ciplinary approach including medical oncologists, ing cell survival instead of cell proliferation, a con- surgical oncologists, radiation oncologists, his- ventional function of EGFR [11]. The mutated topathologists and basic molecular oncologists EGFR is significantly more susceptible to gefitinib will be needed to explore the growing field of inhibition than the wild-type counterpart [8,9,11]. molecular biology and targeted therapy. These discoveries not only revealed the mystery of Discovery of the EGFR mutation within gefitinib response, but also changed the funda- NSCLC is certainly exciting in regard to under- mental view of lung cancer biology and carcino- standing lung cancer carcinogenesis and molecu- genesis. This finding indicates that first, a small lar response to gefitinib. It also raises the percentage of NSCLC is caused by and dependent question of the importance of determining upon a single somatic gain-of-function mutation EGFR mutation status before gefitinib is admin- of a single gene, EGFR; and second, targeting the istered for the treatment of NSCLC patients. mutant gene by inhibition through small organic Indeed, patients may request to know their molecules can lead to control of the tumor and EGFR mutation status before taking gefitinib. clinical remission. This is the first solid tumor to Determination of EGFR mutation status will demonstrate a response to targeted therapy for a involve technical and quality assurance issues. It membrane receptor-based cellular signaling path- should be noted that erlotinib (Tarceva®, OSI way. A similar therapeutic mechanism was discov- 774, OSI Pharmaceuticals), a similar drug to ered for gastrointestinal stromal tumor (GIST) gefitinib, has recently been approved by the FDA and imatinib approximately a year ago [12,13]. for the treatment of NSCLC patients.

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