| First Author | Hamad SH | Year | 2022 |
| Journal | Oncogene | Volume | 41 |
| Issue | 25 | Pages | 3423-3432 |
| PubMed ID | 35577980 | Mgi Jnum | J:326554 |
| Mgi Id | MGI:7314347 | Doi | 10.1038/s41388-022-02348-0 |
| Citation | Hamad SH, et al. (2022) TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice. Oncogene 41(25):3423-3432 |
| abstractText | Studies have shown that Nrf2(E79Q/+) is one of the most common mutations found in human tumors. To elucidate how this genetic change contributes to lung cancer, we compared lung tumor development in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 loss, the most common mutations found in human lung tumors, in the presence or absence of Nrf2(E79Q/+). Trp53/p16-deficient mice developed combined-small cell lung cancer (C-SCLC), a mixture of pure-SCLC (P-SCLC) and large cell neuroendocrine carcinoma. Mice possessing the LSL-Nrf2(E79Q) mutation showed no difference in the incidence or latency of C-SCLC compared with Nrf2(+/+) mice. However, these tumors did not express NRF2 despite Cre-induced recombination of the LSL-Nrf2(E79Q) allele. Trp53/p16-deficient mice also developed P-SCLC, where activation of the NRF2(E79Q) mutation associated with a higher incidence of this tumor type. All C-SCLCs and P-SCLCs were positive for NE-markers, NKX1-2 (a lung cancer marker) and negative for P63 (a squamous cell marker), while only P-SCLC expressed NRF2 by immunohistochemistry. Analysis of a consensus NRF2 pathway signature in human NE(+)-lung tumors showed variable activation of NRF2 signaling. Our study characterizes the first GEMM that develops C-SCLC, a poorly-studied human cancer and implicates a role for NRF2 activation in SCLC development. |
