Abstract 921: The Nrf2E79Q activating mutation accelerates growth of pure-small cell lung cancer but not combined small cell lung cancer Tp53floxed/floxed/Cdkn2afloxed/floxed mice
Authors: Hamad Samera , Montgomery Stephanie A. , Simon Jeremy M. , Bowman Brittany M. , Spainhower Kyle B. , Murphy Ryan M. , Witkiewicz Agnieszka , Fenton Suzanne E. , Randell Scott H. , Hayes Neil , Knudsen Erik , Oliver Trudy G. , Major Ben , Weissman Bernard E. 
Published: June 2022

Inactivating mutations in TP53/P16 are found in most types of non-small cell lung cancer while RB1/P16 losspredominates in small cell lung cancer (SCLC). NRF2 activating mutations are also found frequently in lungcancer, especially in lung squamous cell carcinoma. However, how concurrent mutations in these genes maycontribute to lung cancer development is not fully understood. To address this problem, we compared lung tumordevelopment in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 deficiency, +/- expressionof one of the most common mutations in NRF2 found in human tumors, Nrf2E79Q/+. Surprisingly, both groups,Nrf2E79Q/+ and Nrf2+/+, developed combined-SCLC (C-SCLC): a mixture of SCLC and large cell neuroendocrine(NE) carcinoma along with pure-SCLC (P-SCLC). The appearance of C-SCLC implicates Trp53/p16 double lossin the development of this type of lung cancer. Both groups developed C-SCLC at the same penetrance andincidence; all tumors labeled positive for NE-markers by immunohistochemistry (IHC) including ASCL1, SYP andINSM1. However, C-SCLCs developed by Nrf2E79Q/+ mice did not show NRF2 labeling by IHC, despiterecombination of the Nrf2E79Q/+ allele. In contrast, the Nrf2E79Q/+ mice showed significantly higher incidence of P-SCLC compared to Nrf2+/+ mice. All P-SCLC from Nrf2E79Q/+ mice were NRF2-positive by IHC, while the fewtumors developed by Nrf2+/+ mice were negative. All P-SCLC lesions labeled positive for NE-markers includingASCL1, CGRP & SYP. Both C-SCLCs & P-SCLCs were positive for NKX1.2 (lung cancer-marker) and negativefor P63 (squamous cell-marker). Interestingly, phospho-RB1 was positive for both C-SCLCs & P-SCLCs,suggesting the loss of p16 in our GEMM inactivates Rb1 through loss of inhibition of the cyclin dependent kinases4/6 (CDK4/6). This is the first study showing that the concurrent inactivation of Trp53/p16 in mice drivesdevelopment of C-SCLC. Our study also implicated activation of NRF2 signaling in the progression of SCLC.Our next studies will dissect the mechanisms by which NRF2 activation contributes to the development of SCLCdevelopment.

Citation Format: Samera Hamad, Stephanie A. Montgomery, Jeremy M. Simon, Brittany M. Bowman, Kyle B. Spainhower, Ryan M. Murphy, Agnieszka Witkiewicz, Suzanne E. Fenton, Scott H. Randell, Neil Hayes, Erik Knudsen, Trudy G. Oliver, Ben Major, Bernard E. Weissman. The Nrf2E79Q activating mutation accelerates growth of pure-small cell lung cancer but not combined small cell lung cancer Tp53floxed/floxed/Cdkn2afloxed/floxed mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 921.