ABSTRACT
Within the last decade, there has been a rapid influx of knowledge with respect to the key molecular biomarkers involved in the oncogenesis of NSCLC. This field was paved initially with the success of the ABL tyrosine kinase inhibitor imatinib for the treatment of chronic myeloid leukemia [5]. By understanding how specific genetic lesions promote proliferation in cancer cells, the original paradigms of nonspecific chemotherapy have shifted toward more targeted therapies leading to dramatic improvements in response [6]. In NSCLC, this was first illustrated in a small subset of patients having activating mutations within the epidermal growth factor receptor (EGFR) leading to the initiation and maintenance of lung cancer. Lynch et al. demonstrated the correlation between specific mutations in the EGFR gene with clinical responsiveness to the tyrosine kinase inhibitor gefitinib [7]. Treatment of these patients with reversible EGFR tyrosine kinase inhibitors (TKIs), has led to a superior response rate and progression-free survival when compared with conventional chemotherapy [6, 8]. Subsequently, Soda et al. in 2007 identified another “driver mutation” in a very small subset of patients with NSCLC: the fusion between the 5′ portion of EML4 (echinoderm microtubule-associated like-protein 4) and the 3′ portion of ALK (anaplastic lymphoma kinase) [9]. These fusions are the result of inversions within the short arm of chromosome 2 and currently appear to be novel to NSCLC [10, 11]. The importance of this discovery is highlighted by new agents that target this unique chimeric protein. In this chapter, we will review the biology and treatment of EML4-ALK and other ALK gene rearrangements in NSCLC. 16.2 The Identification of EML4-ALK in NSCLC
Anaplastic lymphoma kinase translocations in NSCLC were first detected in 2007 with the use of a retroviral complementary DNA expression library from a resected NSCLC tumor diagnosed in a 62-year-old Japanese male smoker whose tumor was negative for the KRAS and EGFR mutations. The EML4 and ALK genes both map to the short arm of chromosome 2p (2p21 and 2p23 respectively) in opposite orientations separated by approximately 12 megabases (Mb) (see Fig. 16.1) [9]. The segment encompassing these two loci must become inverted to generate the EML4-ALK fusion gene. In this
particular specimen, the EML4 gene was interrupted at a position 3.6 kb downstream of exon 13, inverted, and ligated approximately 300 bp upstream of ALK exon 20 [9]. Soda et al. successfully amplified this genome fragment containing the fusion point between the EML4 and ALK genes, proving the presence of inv(2)(p21p23) in the cancer cells.
