Elevated murine HB-EGF confers sensitivity to diphtheria toxin in EGFR-mutant lung adenocarcinoma.

Conditional ablation of defined cell populations in vivo can be achieved using genetically engineered mice in which the human diphtheria toxin (DT) receptor (DTR) is placed under control of a murine tissue-specific promotor, such that delivery of diphtheria toxin selectively ablates cells expressing the high-affinity human DTR. Cells expressing only the endogenous low-affinity mouse DTR are assumed to be unaffected. Surprisingly, we found that systemic DT administration induced rapid regression of murine EGFR-mutant lung adenocarcinomas in the absence of a transgenic allele containing human DTR. DT enzymatic activity was required for tumor regression, and EGFR-mutant tumor cells were the primary targets of DT toxicity. In FVB mice, EGFR-mutant tumors upregulated expression of HB-EGF, which is the DTR in mice and humans. HB-EGF blockade with CRM197, an enzymatically inactive DT mutant, partially abrogated DT-induced tumor regression. These results suggest that elevated expression of murine HB-EGF (low-affinity DTR) confers sensitivity to DT in EGFR-mutant tumors, demonstrating a biological effect of DT in mice lacking transgenic DTR alleles and highlighting a unique vulnerability of EGFR-mutant lung cancers.