The EML4–ALK fusion is a result of an inversion on the short arm of chromosome 2 and places the amino-terminal portion of EML4 upstream of the intracellular kinase domain of ALK. Constitutive activation of the kinase results from EML4–ALK dimerization through the coiled coil domain of EML4. The authors expressed this protein in mouse lungs using a fragment of the promoter of surfactant protein C, which is specifically expressed in type 2 alveolar epithelial cells. They established two transgenic lines from seven founder lines, and found that all transgenic mice developed numerous small lung adenocarcinomas a few weeks after birth. Immunohistochemistry and western blotting, as well as pathological and computed tomography examination, indicated that expression of EML4–ALK was responsible for driving the development of NSCLC in these mice.
Several ALK inhibitors have been developed and treatment with one of these, a 2,4-pyrimidinediamine derivative with high specificity for ALK, reduced tumour formation in the mice over a period of 2 months. To further confirm the efficacy of targeting ALK, the authors injected nude mice with mouse 3T3 cells overexpressing EML4–ALK. Of the untreated mice, 90% died 1 month after injection as a result of growth of these cells within the lungs inducing respiratory failure, whereas all mice treated with the ALK inhibitor survived this 1 month period.
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