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A recent spate of papers documenting new translocations in solid tumours in humans has necessitated investigations in mice to show that these mutations are cancer causing. Following from their discovery in 2007 of the EML4 – ALK fusion gene in some patients with non-small-cell lung cancer (NSCLC), Manabu Soda and colleagues have now shown that this lesion is oncogenic in mice.

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.

So, targeting ALK looks promising for the treatment of patients with EML4–ALK-positive NSCLC. However, the authors note in their discussion that the transgenic mice treated with the ALK inhibitor retained small numbers of EML4–ALK-positive cells after the adenocarcinomas regressed and that these mice relapsed after cessation of treatment. Therefore, combined therapies might provide the best treatment strategy for EML4–ALK-positive NSCLC.