PERSPECTIVE 10.1517/1479-6694.1.3.319 © 2005 Future Medicine Ltd ISSN 1479-6694 Future Oncol. (2005) 1(3), 319–322 319 For reprint orders, please contact: reprints@futuremedicine.com Crossing the rubicon in lung adenocarcinoma: the conundrum of EGFR tyrosine kinase mutations Rafael Rosell † , Enriqueta Felip, Noemí Reguart & Teresa Moran † Author for correspondence Catalan Institute of Oncology, Medical Oncology Service, Scientific Director of Oncology Research, Hospital Germans Trias i Pujol, Ctra Canyet, s/n 08916 Badalona (Barcelona), Spain Tel.: +34 93 497 89 25; Fax: +34 93 497 89 50; rrosell@ns.hugtip.scs.es Keyowrds: adenocarcinoma, epidermal growth factor, non- small cell lung cancer, tyrosine kinase mutations Chemotherapy in lung cancer: the state of the art In 2004 in Europe, there were an estimated 2,886,800 cases of cancer diagnosed, including data recorded in the 25 member states of the European Union. Lung cancer was the most common form, with a total of 381,500 cases (13.2%) and an estimated mortality of 341,800 cases (20% of the total) [1]. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC), and the majority of patients present with advanced disease, with dismal prognosis. A landmark study in NSCLC showed that the com- bination of gemcitabine (Gemzar ® ) plus cisplatin attained a median survival of 9.1 months in com- parison with 7.6 months with cisplatin alone [2]. A Phase III trial of the European Organization for Research and Treatment of Cancer (EORTC) showed similar results with paclitaxel (Taxol ® )– cisplatin and gemcitabine–cisplatin, with median survival times of 8.1 and 8.9 months, respec- tively. A third arm of paclitaxel–gemcitabine showed a shorter survival of 6.7 months [3]. A recent meta-analysis, which included a study encompassing 4556 patients, showed a median survival of 9 months for gemcitabine-based chemotherapy in contrast with 8.2 months for non-gemcitabine combinations [4]. One of the mechanisms of tumor resistance to cisplatin is increased nucleotide excision repair (NER) activ- ity, in particular increased levels of excision repair cross-complementing (ERCC)1. The 5´ incision made by the ERCC1–xeroderma pigmentosum group F (ERCC1–XPF) complex is thought to be a rate-limiting step in the NER pathway, as dem- onstrated by an increase in excision activity in extracts from non-cisplatin-resistant cells after addition of purified ERCC1–XPF protein, com- pared with no increase in excision activity after addition of ERCC1–XPF to extracts from cisplatin-resistant cells [5]. The potential use of ERCC1 mRNA expression as a predictive marker for the effectiveness of cisplatin-based chemo- therapy is an important area of clinical transla- tional research. Together with ERCC1, ribonucleotide reductase (RR) subunit M1 is also involved in gemcitabine metabolism as a participant in the NER pathway, providing nucleotides that fill gaps created by ERCC1 excision of the DNA strand-containing cisplatin bulky adducts. Tumor overexpression of RRM1 mRNA in gemcitabine/cisplatin-treated NSCLC patients was associated with a short median survival of 3.6 months in contrast with 13.7 months for patients with low RRM1 mRNA expression (p = 0.009) [6]. This data brings a new era of customized chemotherapy based on NER transcripts. Activating mutations in tyrosine kinases The concept that a rare population of tissue stem cells may be the cellular origin of cancer was pro- posed almost 150 years ago [7]. In models of tumor drug resistance, mutations in the surviv- ing tumor stem cells may arise by mechanisms such as point mutations, gene activation or amplification, which confers a drug-resistant phenotype [8]. In many types of cancers, muta- tions in genes that activate cellular signal trans- duction pathways (protein kinase B [Akt] and signal transduction and activator of transcription [STAT]) contribute to enhanced proliferation and survival of cancer cells. One well-defined example is mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR). EGFR-mutant lung cancer cells exhibit increased sensitivity to disruption of Akt- and STAT-mediated antiapoptotic signals but increased resistance to cell death signals induced by the commonly used chemotherapeutic agents such as cisplatin [9]. The tyrosine kinases are attractive candidates for molecularly targeted therapy in cancer, since cancers become depend- ent on growth signals from the mutant tyrosine kinases. Tyrosine kinases require ATP for their enzymatic activity, and small molecules that mimic ATP may bind to mutant kinases and inactivate them [10]. Recently, inhibition of tyrosine kinases by selective small molecule inhibitors has emerged as a new strategy for the treatment of hematologic malignancies and solid tumors, including leukemias, gastrointestinal stromal cell tumors (GISTs) and NSCLC. Imat- inib inhibits the constitutively activated form of the Kit receptor tyrosine kinase that is mutated in the majority of GISTs [11]. Platelet-derived