Resistance to chemotherapy in non-small cell lung cancer with Keap1 gene mutation

We report the case of a 49-year-old Japanese man with advanced non-small cell lung carcinoma showing a Keap1 gene mutation. Although he received platinum-based first- and second-line chemotherapies, he was judged to have progressive disease because of the appearance of new bone metastasis. Immunohistochemical analysis revealed the strong nuclear expression of NF-E2 related factor 2 (Nrf2) with higher expression of detoxification enzyme and drug efflux pump genes in the tumor cells. We detected a mutation associated with amino acid substitutions in Keap1 of the DGR/Kelch domain, the Nrf2 binding region. No EGFR gene or KRAS gene mutation was detected. These results suggest that a dysfunctional mutation of the Keap1 gene caused constitutive activation of Nrf2. In this case, activation of Nrf2 might relate to chemoresistance via induction of its target genes, such as detoxification enzyme and drug efflux pump genes.