Lung cancer is one of the most common causes of cancer death, making development of novel therapies for this disease a priority. One strategy to progress this endeavour is to investigate the function of different cell populations in lung tumours. This can be achieved by using diphtheria toxin (DT), an exotoxin secreted by Corynebacterium diphtheriae, to ablate specific cell populations in mice. This strategy has been widely used in a range of genetically engineered murine models of disease and relies upon selective expression of human DT receptor (DTR), which has a higher affinity for DT compared to the mouse homologue, in target cell populations to confer sensitivity to DT. However, off-target effects have been observed in wild-type (WT) mice, including lung inflammation, weight loss, proteinuria and cochlear damage. Therefore, cautious investigation is required to determine whether DT has any unintentional biological effects that could perturb in vivo studies of disease, including lung cancer.

In our current issue, Camila Robles-Oteiza, her mentor Dr Katerina Politi and colleagues unexpectedly found that DT caused mutant EGFR-driven lung adenocarcinoma regression in mice that lacked the transgenic DTR allele. Mice expressing mutant EGFR developed lung tumours; however, administration of DT induced apoptotic tumour cell death in mice that were expressing human DTR as well as mice that were not. The authors found that this action was dependent on the enzymatic activity of DT, as tumour regression did not occur when using an enzymatically inactive mutant of DT. This inactive mutant remains capable of causing inflammation; therefore, tumour regression was not due to an inflammatory response to DT. The anti-tumour effect of DT was strain specific, with sensitivity to DT in tumours of FVB mice, but not those of C57BL/6 mice. Fascinatingly, comparison of these strains showed that the EGFR-mutant lung adenocarcinomas upregulated murine DTR, sensitizing tumours to DT in FVB mice.

Politi and colleagues have highlighted an unexpected observation that underscores the need for attention and consideration when using DTR approaches in murine disease modelling. Subsequently, they have uncovered a mechanism that may be relevant for development of novel therapies for lung cancer. DT and its inactive mutant have previously been investigated as potential cancer therapies. This study suggests that tumours with increased DTR expression, such as certain lung adenocarcinomas, could be particularly susceptible to DT therapy.

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