Abstract 1168: From clinical mutational data to a novel lung cancer mouse model -NF1inactivation cooperates withRASA1inactivation to drive non-small cell lung cancer (NSCLC)

Abstract

Abstract 11% of non-small cell lung cancer (NSCLC) patients harbor NF1 mutations. The enrichment of NF1 mutations in lung adenocarcinoma (LUAD) cases that otherwise lack activated oncogene mutations indicates that NF1 loss may play a necessary role in the activation of the RAS pathway. However, conditional, biallelic loss of Nf1 in the mouse lung is insufficient for LUAD initiation over 2 years, indicating additional genetic or epigenetic events cooperate with Nf1 loss in lung tumorigenesis. To better understand NF1 mutant lung cancers, we analyzed a lung cancer dataset with 47227 patients’ genomic mutation data from Foundation Medicine (FMI) and found that NF1 mutations (5270 patients) are associated with a higher mutational burden compared to NF1 wild type lung cancer patients in the lung cancer patients’ clinical database. We then analyzed the AACR GENIE non-small cell lung cancer datasets for genes mutated concurrently with NF1 mutation. We found that NF1 mutation statistically significantly cooccurs with RASA1 (p <0.001 for concurrency) and with TP53 mutations in the non-small lung cancer dataset. NF1-mutated samples lack other key driver oncogene mutations such as EGFR (p <0.001 for mutual exclusivity). To functionally validate our findings of genetic cooperativity, we conditionally deleted the two key GAPs: Nf1 and Rasa1 (with Trp53) in vivo. Deletion of both Nf1 and Rasa1 but neither the Nf1 or Rasa1 deletion alone lead to LUAD when combined with Trp53 deletion. Our new mouse model provides a unique tool for our ongoing effort to understand the mechanism of Nf1 & Rasa1 tumor initiation in the lung and will aid preclinical investigations of targeted therapies. Citation Format: Lin Song, Thaidy Y. Rodriguez, Adam Olshen, Eric Collisson. From clinical mutational data to a novel lung cancer mouse model -NF1inactivation cooperates withRASA1inactivation to drive non-small cell lung cancer (NSCLC) [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 1168.