ALK rearrangements were identified in none small cell lung cancer (NSCLC) in 2007 by two independent groups. Soda et al. developed retroviral-based cDNA expression libraries to screen for novel oncogenes. They transfected a cDNA library derived from a lung adenocarcinoma from a 62-year-old Japanese male smoker who was prescreened to be negative for KRAS and EGFR mutations. They identified an echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (EML4-ALK) fusion transcript that possessed transforming activity in 3T3 cells. 3T3 cells transfected with EML4-ALK and implanted in nude mice resulted in rapid tumor growth; an ALK inhibitor inhibited the growth of BA/F3 cells transfected with EML4-ALK. Finally, a preliminary survey of a panel of 33 NSCLC tumors revealed that EML4-ALK rearrangement occurs independently of EGFR and KRAS mutations. To further demonstrate the role of EML4-ALK in the pathogenesis of NSCLC, Soda et al. generated transgenic mice engineered to specifically express EML4-ALK in lung alveolar cells, which resulted in hundreds of lung adenocarcinoma nodules. Treatment of these transgenic mice with an ALK inhibitor resulted in reduced tumor burden compared with untreated mice. Intravenous injection of EML4-ALK/3T3 cells resulted in massive infiltration of EML4-ALK/3T3 cells in the lungs of nude mice and rapid death of the majority of the mice within 1 month. Treatment with the same ALK inhibitor resulted in the absence of EML4-ALK/3T3 cells in the lung and prolonged survival. In summary, Soda et al. convincingly demonstrated that EML4-ALK is a unique driver mutation in none small cell lung cancer (NSCLC) and that inhibition of EML4-ALK activity in vivo led to the reduction of lung cancer burden. Contemporaneously, Rikova et al. characterized the phosphotyrosine profile in 191 none small cell lung cancer (NSCLC) cell lines and tumor samples using a phosphoproteomic approach to identify "driver kinases" in none small cell lung cancer (NSCLC). They identified a high level of ALK phosphorylation in several none small cell lung cancer (NSCLC) tumor samples and H2228 none small cell lung cancer (NSCLC) cells. Rapid amplification of the 5′ complementary DNA ends (5′ RACE) of the RNA transcripts isolated from these samples with highly phosphorylated ALK revealed the EML4-ALK fusion transcript. No mutations were found in the ALK kinase domain. Thus, two groups using two different approaches independently identified ALK translocation, the first of its kind in a common solid malignancy.
Ou S-HI, Bartlett CH, Mino-Kenudson M, Cui J, Iafrate AJ. Crizotinib for the Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology. The Oncologist. 2012;17(11):1351-1375. doi:10.1634/theoncologist.2012-0311.